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J) 



EuropSisches Patantamt 
@ ^JJJ European Patent Office 

Office europden des brevets (g) publication number: 0 661 259 A1 




@ EUROPEAN PATENT APPLICATION 

@ Application number: 95100033.0 @ inL Cl«: C07C 233/81, C07C 235/84, 

@ Date of filing : 02.01.95 C07C 69/76. C07C 63/66. 

C07C 327/32, C07C 327/26, 
C07C 323/22. C07C 327/48. 
C07C 229/60. C07C 229/38, 
C07C 65/38. C07C 69/92. 
C07C 59/72, A61K 31/165, 
A61K 31/19. A61K 31/235. 
A61K 31/265 



@) Priority : 03.01.94 US 176746 
23.03.94 US 216740 
19.09.94 US 306092 

@ Date of publication of application : 
05.07.95 Bulletin 95/27 

@ Designated Contracting States : 

AT BE CH DE DK ES FR GB GR IE IT U LU MC 
NL PT SE 

(fi) Applicant : BRISTOL-MYERS SQUIBB 
COMPANY 
P.O. Box 4000 

Princeton. NJ 08543-4000 (US) 



@ Inventor: Stanrett Jr., John E. 
23 Hawks Nest Circle 
Middletown, CT 06457 (US) 
Inventor: Yu, Kuo-Long 
139 Tread well Street 
Hamden. CT 06517 (US) 
Inventor: Mansuri, Murammll M. 
201 Art)oretum Way 
Burlington. MA 01803 (US) 
Inventor : Tortolanl. David R. 
19 Abbey Lane 
Merlden, CT 06450 (US) 

@ Representative : Kinzebach. Werner. Dr. et al 
Patentanwalte 

Reitstottar. Kinzebach und Partner 
Postfach 86 06 49 
D-81633 Munchen (DE) 



@ Substituted (5,6)-dihydronaphthalenyl compounds having retinoid-like activity. 
@ The present inventk>n relates to a compound of formula I 




CD 



a. 

UJ 



or a nontoxic phamnaceuticaHy acceptable salt, physiologically hydrolyzable ester or solvate thereof, in 
which 

X is ^CO-. -NH-CO-. -CS4^H-. -C0-0-, -COS-. -SCO-, -SCHr, -CH2-CH2-, -C^C-. 

-CH2-NH-, -COCH2.. -NHCS-. -CH2S-. .CH2O-. -OCH2-, -NHCH2- or ^R5=CR«- ; 
are Independently hydrogen, halogen, C, ^alkyl, hydroxy. C, galkyloxy or nitro ; 
is zero or one ; 

is -(CH2)rY, Cv^lkyl. or Caoecydoalkyi ; 



d> 

m A 

CM 

^ R-" and R* 



n 



Jouve. 18. rue Sahl-Oenis. 75001 PARIS 



EP 0 661 259 A1 



K . ^ Ci_ealkyl, CH2OH. -CONHRy, or CHO ; 

and R3 are independently hydrogen or Ci_ealkyl ; 
a 'i^fcafof Ihe^for^ST^'^^"*'^ hydrogen or ,alkyl ; but when n is one, R* and R"* together can fom 




Y is n^hthyl or phenyl, both radicals can be optionally substituted with one to three same 

or dffferent C, salM or halogen ; 
2 is hydrogen or Ci.ea^M ; 

R', R« and Rf are independently hydrogen or Ci»«alkyl ; and 
t is zero to sbc 

^w.^xHa^^'^ invention are methods for preventing and/or treating tumors and non^alignant 
2?rr«L!2itIi^^'?'^ administenng a compound of fonmula I to a mammal. Further provided Is a 
SS^'a^XlSS? "^"^ " Of , in aa^re w«h (a, 



2 



EP0 661 259 A1 



The present Invention provides compounds having relinoid-like activity. More specifically, the compounds 
of the present invention are useful for preventing and/or treating various skin disorders, such as, but not limited 
to, acne, psoriasis and damage from inradiatk>n. Further, they have antitumor activities. 

5 BACK6R0UN D OF THE INVENTION 

Retinoic add and its natural and synthetic analogues (retinoids) exert a wide array of biological effects. 



10 



IS 



20 




COOH 



25 



Retinoic Acid 

They have been shown to affect cellular growth and differentiation and are promising drugs for the treat- 
ment of several cancers. Roberts. A.B. and Sporn. M.B. in -The Retinoids." Sporn, M.B.. Roberts. A.B.. and 
Goodman, D.S., eds. 1984. 2, pp. 209-286. Academic Press. New York; Uppman. S.M.. Kessler. J.F., and 
Meyskens, F.L, CancerTreat Rep.. 1987. 71. p. 391; ibid,, p. 493; Hong. W.K. et al.. N. EngL J. Med 1990 
32i p. 795; Huang. M. et al.. B/oocf. 1988, 72, p. 567. Afew retinoids are already in clininal use in the treatment 
of dermatological diseases such as acne and psoriasis. For example, isotretinoin Is used clinically for oral ther- 
apy of severe acne, and etretinate is particularly useful In the treatment of psoriasis. Orfanos C E EhlerL 
R., and Gollnick, H., Drugs, 1987, 34, pp. 459-503. 



30 



\>^^ COOH 



CH3O' 




OOCgHs 



ISOTFETINOIN 



ETRETINATE 



35 other examples of retinoid compounds include arotinokl of formula II and retlnobenzoic acid of formula III 
in which Q equals -NHCO-, -CONH-. -COCH=CH-. -CH=CHCO-, -COCHr. etc. 



40 



45 




COOH 



II 



III 



See for example: Loeliger, P., Bollag, W.. and Mayer. H.. Eur. J. Med, Chem, 1980, 15, pp. 9-15; Kagechika 
so H. et al., J. Med Chem., 1988, 31, No. 11, pp. 2182-2192. ~ 

SUMMARY OF INVENTION 

The present invention relates to a compound of formula I 



3 



EP0 661 259 A1 



5 




or a nontoxic pharmaceuticatly acceptable salt, physiologically hydrolyzable ester or solvate thereof in which 
X is -O-CO-, -NH-CO- -CS-NH-. -CO-O-. -CO-NH-. -COS-, -SCO-, -SCHj-. -ck-CH,- 

-OC. -CHrNH.. -COCHr. ^HCS-. -CH^S.. -CH.O-. -OCHr, -NHCHr or ^RfcCfVL; ' 
are independently hydrogen, halogen. C,^kyl. hydroxy, C,^a!kyloxy or nitro; 
Is zero or one; 

is -(CHaVY, Ci^alkyl, or Ca^cydoalkyl; 
Is -CQaZ, Ci^kyl, CH2OH, -CONHRy. or CHO; 
are independently hydrogen or C,_ealky!; 

are Independently hydrogen or C,^lkyl; but when n is one. R- and R»» together can form 
a radical of the fonmula 



R" and R^ 
IS n 
R^ 
R^ 

R2and R3 
R« and R^ 



25 




Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same 

or different Ci_ea1kyl or halogen; 
30 ^ »3 hydrogen or Ci^lkyl; 

R6, Re and Rr are independently hydrogen or Ci^alkyl; and 
t is zero to six. 

Also provided by this Invention are methods for preventing and/or treating tumors and non-mallgnant skin 
disorders comprising administering a compound of formula I to a mammal. Further provided is a pharmaceutical 
35 formulation (composition) comprising a compound of formula I in admbcture with (a) pharmaceutically accent- 
able excipient(s). ^ 

BRIEF DESCRIPTION OF THE DRAWING 

^ Figure 1 . 2 and 3 are the (^toxicity dose response curves for lung line L2987. 

DETAILED DESCRIPTION OF THE INVENTION 

The present Invention relates to a compound of formula I 

45 



Ra 



50 



55 




^R3 



or a nontoxic pharmaceutically acceptable salt, physiologteally hydrolyzable ester or solvate thereof in which 
X is -O-CO-, -NH-CO-. -CS-NH-. -C0-0-. -CO-NH-. -COS-. -SCO-. -SCH,-. -CH^-CH^ 

.C-C-. -CHrNH-. -COCHz-, -NHCS-. -CH^S-. -CH^O.. -OCHr. -NHCHr or -CR^^CR^ 



4 



EP0 661 259 A1 



R«» and R"* are independently hydrogen, halogen, C^^kyl. hydroxy. Ct-ealkytoxy or nitro; 

n is zero or one; 

is -(CHiVY. C,^llcyl, or Ca-^cydoalkyl; 

is -CPaZ. Ci^kyl, CH2OH. -CONHRy, or CHO; 
R2 and R3 are independently hydrogen or Ci^aikyl; 

R» and W> are independently hydrogen or C,^llcyl: but when n is one, R» and Rb together can form 

a radical of the formula 



c ■ 



Y is naphthyl or phenyl, both radicals can be optionally substituted with one to three same 

or different Ci^alkyl or halogen; 
Z Is hydrogen or Ci^lkyl: 

R*. R* and Ry are Independently hydrogen or C,^alkyl; and 
t Is zero to six. 

In the Instant application, the numbers in subscript after the symbol "C" define the numberof caibon atoms 
a particular group can contain. For example. C,^lkyl refers to straight and branched chain alkyi groups with 
one to SIX carbon atoms and such groups include methyl, ethyl, n-propyl. isopropyl. n-butyl. t-butyl. n-pentyl 
n-hexyl. 3-methylpentyl. or the like alkyI groups; C^^doalkyl refers to «sydopropyl. cylcobutyJ. cydopentyl' 
or cydohexyl: and halogen refers to fluorine, chlorin e. bromine, or iodine. In the instant applkiatton aU symbols' 
once defined retain the same meaning until they are redefined. 

Some compounds of formula I may also fomi phamiaceuticaily acceptable metal and amine salts in whteh 
the cation does not contribute significantly to the toxicity or biological activity of the salt These salts are also 
part of the present inventton. Suitable metal salts include the sodkiro. potassium, calcium, barium, zinc, and 
aluminum salts. The sodium or potassium salts are preferred. Amines which are capable of forming stable salts 
group Indude trialkylamlnes such as triethytamlne. procaine, dibenzylamlne, N-benzyl-p-phenethylamine 1- 
ephenamine, N.N'-dibenzylethylenediamlne. dehydroabietylamine. N-ethylpiperidine. benzylamine. dteydo- 
nexylamine, or the like pharmaceutically acceptable amines. 

When compounds of formula I contains carboxy groups, it can form physiologically hydrdyzable esters 
which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. They are pre- 
ferably administered orally since hydrolysis In many instences occure prindpany under the influence of the di- 
gestive enzymes. Parenteral administratkm may be used where the ester perse is active, or in those instances 
where hydrolysis occurs in the Mood. Examples of phystologically hydrolyzable esters of compounds of formula 
I indude C,^lkyl, benzyl, 4-methoxybenzyl, Indanyl. phthalldyl, methoxymethyl, C,^alkanoyloxyC,^lkyl, e g 
acetoxymethyl, pivaloyloxymethyl orproplonyloxymethyl, C,^koxycarbonylQxyC,^lkyl. e.g. methoxycarbo- 
nyloxymethyl or ethoxycarbonyloxymethyl. glycyloxymethyl, phenylglycyloxymethyl. (5-methy|.2-aco-1-3-di- 
oxolen.4.yl)-methyl and other well-known physiologically hydrolyzable estere used, for example, in the peni- 
cillin and cephalosporin arts. Such esters are prepared by conventional techniques known In the art 

The structural formulae as drawn in the instant application are believed to best represent the structures 
of compounds of the present im/entk»n. However, some compounds within the scope of the Invention may exist 
as other tautomeric forms, in whldi hydrogen atoms are transposed to other parts of the molecules and the 
chernical bonds between the atoms of the mdecules are consequently rearranged. It should be underetood 
that the structural formulae represent all tautomeric forms, insofar as they may exist 

The synthesis of a compound of formula I can be accomplished by a wide variety of methods using con- 
ventional starting materials and processes. The synthetic descriptkuis and specific examples that follow are 
only intended for the purpose of illustration, and are not to be construed as Rmiting in any manner ways to 
make compounds of the present invention by other methods. 

TypteaHy a compound of formula I can be made by employing one of the processes or obvious variations 
thereof as depicted in Sdiemes I to XXII. All the steps in Schemes I to XXil are standard processes which can 
be easily practiced by anyone skilled in the art. The spedf ic examples that are provided after the Schemes 
are intended to illustrate spedf ic conditions which may be employed to carry out certain steps in the Schemes 
and are not to be construed as limiting the conditions in any way. 

In the Schemes, R' is a conventional caiboxy protecting group: It is preferably C^ialkyl or phenyl- even 



EP0 661 259 A1 



more preferably R7 is phenyl, methyl, ethyl or t-butyl. When radical is t-l«jtyl. it can be removed by trifluor- 
oacetlc acid. 

In Step (a) of Scheme IV, a compound of formula XVIII Is reacted with at least two equh^alents of R^LI in 
which R« is as previously defined, but preferably primary C,^lkyl (When a compound of formula XIX in which 
R5 is hydrogen is desired. It is preferable to employ a reducing agent which converts a carboxyllc acid residue 
to an aldehyde on a compound of formula XVIII. Many such reducing agents are well known in the art) Sub- 
sequently, an anion of p-I(diethoxyphosphoryl)methyl]benzene derivative of fomiula XX can be reacted with 
a compound XjX In a routine Horner-Wadsworth-Emmons reaction (see: Org. React., 25. 73-253 (1977); Stec. 
^cc. Chem. Res., 411-417 (1983)) to afford additional compounds of fbmiula l^. Subsequent hydrolysls yields 
a compound of formula I"*. Alternatively, a compound within the scope of formula l« can be made by a process 
of Scheme IV^. In Scheme V. R» is a phenolic hydroxy protecting group, such as t-butyldlmethylsliyl which can 
be removed by tetrabutylammonium fluoride (TBAF). 

Starting compounds of general formula XVIII in Schemes III. IV, VI, Vil. XI, XII and XIII can be prepared 
by a wide variety of methods using conventional starting materials and processes. The syntheses of certain 
compounds within the scope of formula XVIII are illustrated in Schemes XIX to XXII. 

SCHEME I 




OEt 



Step (a) 




S(ep(b) 




Step (c) 



Step(d) 




VI 



VII 




SOO, 




<>'20CH5CH^iCCHj)3 

COpR' 



Slep(e) 




(0 




IX 



6 



EP0 661 259 A1 

SCHEME II 






40 



45 



SO 



55 



7 



EP0 661 25dA1 



SCHEME III 



10 




1) SOCI2 



2) 




COgR^ 



Pyridine 
Step (a) 



15 



20 




2S 




8 



EP0 661 259 A1 



SCHEME IV 




9 




10 



EP0 661 259 A1 



SCHEME V 

5 



o 




I' 18 

40 



45 



SO 



55 



11 



EP0 661 259 A1 



SCHEME VI 



XVIII 




-OR' 



l9 



llO 



SOCI2 orCICCXX)CI 



2) HO 



XXVIII 



Step (a) 



Hydrolysis 



Step (b) 




Scheme VII 




12 



EP0 661 259 A1 




13 



EP0 661 259 A1 



Scheme IX 




SO 



14 



EP0 661 259 A1 

Scheme X 




15 



EP0 661 259 A1 



5 



10 




XVIII 



18 



20 



28 



30 



38 



40 



48 



60 



55 



Scheme XI 




LIII 



I OIBAL 




16 



EP0 661 259 A1 




17 



EP0 661 259 A1 

Scheme XI I i 




55 



18 



EP0 661 259 A1 

Scheme XIV 

5 




20 



25 



30 



35 



40 



45 



SO 



55 



19 



EP0 661 25dA1 



5 



10 




VI 



18 



20 



28 



30 



38 



40 



48 



SO 



88 



Scheme XV 




Lxri 



I FeClj/Fe 




I Hydrolysis 




20 



EP0 661 259 A1 

SCHEME XVI 



10 



18 



20 




1. HNOyH^SO, 
2- PtjCVC.Hj 



LXIV 




LXVI 



2. CO, MeOH 
P^OAc)a,dppp 



2. H2SO4 



LXV 




COOMe 



2. R^Sneug 



25 



30 




COOMe 1. NaOH 



LXVIII 



2. (COCO2 

3. 44^H2.Ph-C00R' 
Pyridine 



4. Hydrolysis 



SCHEME XVII 



4S 



SO 




LXIX 



2- R*SaBu3 
Pc^dbag. PhjAs 




LXX 



55 




NHa 1. pO0CPftC00R7 
II pyridine 

2. Hydrolysis 



LXXZ 




131 



21 



EP0 661 259 A1 

SCHEME XVIIl 




22 



EP0 661 259 A1 

SCHEME XIX 




23. 



EP0 661 259 A1 

SCHEME XX 




xviri^ 

SCHEME 



O 




XXXII 



XXI 




24 



EP0 661 259 A1 

SCHEME XXII 




^'^-'"J><^^ 2.PTSOH 



IS 



20 



XXX 

XXXVII 





OH 



_ XXXVIII 

^ xviri^ 

DESCRIPTION OF SPECIFIC EMBODIMENTS 



30 



35 



45 



to variations In order to P^7^<1^2Tt^ZtZ^r'V -<^«Pt«^ 
variations Of the methods to P««Ju3,e siST^m^uL specifically disclosed. Further, 

to one Skilled in the art compounds in som«vhat different fashion will also be evideni 

tetramethylsllane (TMS) as reference steTdart rS^^^^ ^ ^ ^^pressed In parts per million (ppm) versus 
NMR spectral data correspondsrSJeTiTJhtd^r ""e various shifts in the proton 

cule. The nature ofthe shif ts as to mXSLe^^^^^^^^ 
(bt). broad quartet (bq).singlet(strult5^^^^^^^^^ 

blet of triplet (dt). and douWet of oZiV^diT ^^f ^ ' ^ T •'^"blet of doublet (dd). dou- 

(perdeuterodimethylsulfoxid.) orZSi;^^^^^^^ ^"-^ DMSO-d. 



are 

MS : mass spectrometry 
HRMS : high resolution mass spectrometry 
Ar ;aryl ' 

^ DCI : desorption (or direct) chemical ionization 

Hex : hexane(s) 

ffiu : tertlarybutyl 

h : hour(s) 

"^in : minute(s) 

^ Ph : phenyl 

Y : yield 

THF : tetrahydrofuran 

ThO : triflic anhydride (trifluoromethanesuifbnic anhydride) 

25 



EP0 661 259 A1 

SEMa : 2-(trimethylsi|yl)ethoxymethyl chloride 
EXAMPLE 1 

. S>S-D'niethvl ^ihydrofuraf>-2.QnA 



zane solution was heated atreflux for2 hours >Silol^^»ir?^^^^°*''^""^*'°" '"e resulUng ben- 
« acetate (500 mL) weia then added at O'cTe l^^^T"^^'^ """^"""'"^ ^""'^ -"L) and etSJl 

mL dnedoveranhyd^usmagnesiumi fate ZreLaS^^^^ 
punfied by distillation (b.p.. 43-C. 0 35 Ho 

(CDO,): « ft J-si ^^•2H). iSs ft ^8.^1''^^^^^^^^^^^ '-""^-on. (Vile*^- 

^« EXAMPLE 2 

4,4-Dlmethy l-1.tefrafon^ ^/^ 

.hiir*'^'''"'°°^- Phase was J^^^^^^^^^ 

i2"i4Wi. u. 01.77. H, 9.14. Found: C. 81.70; H, 9.12. 

EXAMPLE 3 

4,4.Dimethvl-7- nftfo-1-tetialQnA 
EXAMPLE 4 

4,4-Dimet hyt>7>amino>1-tetralone(Vn ) 
EXAMPLE 5 




COgMe 



EP0 661 25dA1 



10 



mL) and washed with saturated sodium bicarbonate (2 x 200 mL). The organic phase 




EXAMPLES 



15 



20 



28 



30 



3S 




ilum hS^ N.N-dimethylformamide (75 mL) at O'C was treated with 80% so- 

fa 6Ta2w2Lo?'.T'''!i-'^'"^ 

^^'i- After 16 h at room temperature, the mixture was diluted wfth a 10% 

a 1 «s,due chromatographed (elated with 20% ethyl acetate in hexane) over silica to give^J 

SmT", « L ""^ (MH^: iH-NMR (CDCy : 8 7.90 (d J=7.5 Hz. 2H) 7 82 fe 

1H). 7.45 (d. J=7.5 Hz. 2H). 7.25 (m, 2H). 5.22 (bs. 2H). 3.93 (s. 3H), 3.67 (t. J=8.0 Hz 2H 2 69^1=7 0 ti' 
2H). 1.98(1. J=7.0 Hz. 2H). 1.33 (s. 6H). 0.96 (t. J=8.0 Hz. 2H). COO (s. 9H). ^"J- ^-^^ ft J-7.0 Hz. 

EXAMPLE 7 



40 



4S 



HO. ^CHjCHj 




To a solution of compound Xa(1.07g, 2.22 mmol) in anhydrous tetrahydrofuran (15 mL) at -78»C was added 

mWu^^rr ^ " """"" '"''^ ^ •-"°')- After 10 inutes. ft* «fcSJ 

mixture was allowed to warm to room temperature. After 3 hours at room temperature the rearffan mhT.™ 
was diluted with ethyl acetate (1 00 mL) and washed wfth water (100 ^l^Tp^eZf^s^Z 

If 'th?™/ '^w'T.u' °" f""'^" -""^ 20% ethyl acetate Jhexa^ o Z 

9 ^) of the title product: 'H-NMR CDCI,) : 6 7.87 (m. 2H). 7.40 (m. 2H) 7 20 (m 1H) 7 10 (m 7M\ t Anil' 
1H). 5.20 (m, 1H). 3.90 (s. 3H). 3.75 (m. 2H). 2.00 (m, 1H . 1. 78:7.42 (m 5H) T27fe 3m ^s 3m 
(t. J=8.0 Hz. 3H). 0.95 (m. 2H). 0.00 (s. 9H): MS (DO) m/e! 494 (MH*- H^S). ' ^' ''"^ 

ss EXAMPLE 8 

4-[[(5.6-D.hydre-S.5.d.methyl-8^hy|.2.napthalenyt )aminolcart)onvllben2oic acid, methyl ester ( Ha) 



27 



EP0 6612j»A1 



10 



IS 




EXAMPLE 9 



20 



25 



30 



35 



40 



45 



SO 




COgH 



(20 mg was added. The precipitate was ooiiert^rt k *«'"P«ra»"»»- After 72 houre an excess of lisj Hri 




55 



28 



10 



EP0 661 259 A1 

EXAMPLE 11 ^ 

ag'g:gga:g!^^ ^ 




f5 



20 



•n vacuo and the residue chromatographed on sHiL „ J/. ! ^ *'««8'*ton mixture was concentrated 
'T^OCr: 18%)ofthetaiep«Kluct; 'f^NMR VcDaTt « 

in hexane) to aive 2a 

1H). 7.50 (m. 2H). 7.35 (d, J=8.5 Hz. 1H) 5 80 /in i wf^ ^^J^^ ^'^^ -^=9 0 Hz, 2H) 7 90 /bs 

(3, 6H); MS (DCI) m/e: 350 (MH^ ^' '''' ^"^^ ^.25 (m, 2H). 2.10 (d. J=1.4 H^'sH^SO 

EXAMPLE 12 



25 4 



50 




1.18 (s. eH); '»CNMR(DMSold.) 6 166 79 ^LV^Aa^J-^ ^"^ C"' ^' 2-01 (d. J=1 Vjfe 3 m' 

^ EXAMPLE 13 ' . . o. 



40 



(thy 



.no]carUijivllb«n^ nteacid. meth^ ....:r|7;^ 



-2-naphthalen 



55 




29 



10 



EP0 661 259 A1 

reaction mbrture was diluted with ethyl acetate (V(SnnU aS^'h J 7^1 ^'"^ -^8°°. the 

was evaporated and the residue <^ro^toMSZ lv^^^J^,T''''^ '"'->• "^"^ »'S«""= Phase 
gjve 449 mg (Y: 67%) of the title compoundT'H^lJS Ti^cf V 1 rT^f' ^"'^ f^-^"*) «« 

2H). 3.95 (s. 3H). 3.65 (m. 2H). 2.20.zS J 2H) 1 8sS^ ^ Lf f ^ ^O-^-SO (m. 10H). 5.20 m. 

(m. 2H). 0.00 (s. 9HJ; MS (Dci) m/e: 5« {!l;?2'ol ^ ^H). 0.95 

EXAMPLE 14 

HK^-D^.^^»,..^^.,^,..^ _..^.. . 



20 




59 



s*"carx~T.r^^^^^ 

acetate (loO mL) and washed with saturate! so^L mcI^L'T' diluted with ethyl 
concentrated in vacuo and thereslduech^ma^^^^^^ 

2H). 7.90 (m. 1H), 7.65 (m. 1H). 7.40 (m 5H) 6 90 iwf « « f ^H). 7.90 (d. J=8.5 Hz 

Hz. 2H). 1.40 (s. 6H): MS (DCI) mfe: i^S^li? ^ ' -^"^ ^-^^ («• 3H). 2>10 (d. J^^ 

EXAMPLE 15 



J5 



4S 



55 




To a stirred solution of compound IV m 9-f ^r^^i d« 
mg was added 10 N NaOH (2.^1^12; ^^^^^ tetrahyd«,furan solution (5 

(20 mg was added, the precipitete co ected^^cZ^fS'?* f f HO 
9«;e 74 mg (Y: 89%) of the title compound; iH-KSMsi!^ r.n'^a '^"^ ' •^''ed to 

2.1 Hz. 1H). 7.35 (m. 7H). 5.97 (t. J=4 6 4 1H) 2 « u ''"^^ C"' ^H). 7.7e(dd. J=84 

66.70. 164.58. 140.46.^40.33 ^slai.^sJ 62 136 7V?33 ,?\'^^^^^ ^'CNMR <DMSc4, ! 

127.18. 126.83.124.04, 119.84, 118 03 SB ti 'i^S^lL fJ ' ^^^ ""^ ^29.16. 128.42. 128J5. 127 M 
1700. 1652, 153Z ' ^2-^^' 28-04; MS (DCI) m/e: 398 (MH-fc W (KBr): 30^6 29S' 

AnaLcalcdforC«,H2,0,N,.1.54H20:C.73.45 H5 81N3?cip ' ' 

f 0.^0. H, 5.81. N. 3.29. Found; C. 73.05; H. 5.53; N, 3.22 

EXAMPLE 16 

^^::^-rt^^;::t^^^^^^^ n^.o a^d (27.86 mg .luted 

red^Ss;t.r:a%-^^^^^ 
-R(0MSO.d.):a9.15(d..i?Kri^^^^^^ 

30 



EP0S61 259 Al 



10 



He. 2H, 2.07 (, J.r.0 Hz. 2H). t.43 (s. eH); MS (DC.) „.e: 193 (MH* . N^P^ 
EXAMPLE 17 

4.4^ethv».7.h^ roinM.tetralnno / vn/^ 

mL) The combined organic phaLt^rr^n^^^^^ 

^■?i'i?:i.sar'"""^^^ 

EXAMPLE 18 



IS 



20 



25 



35 



To a solution of compo und XIV f6flo m« 
methanesulfonic anhydride (4.427SL|. 0 74 ''"t^""TT "^^ "'^^ 

room temperature. After 16 hours IN Ha lol n,. . * ° ^« ^eactton mixture was then allowed to »««-T 
(2 X 50 mL). The combined C'lc ^^e fl^S o^ 

EXAMPLE 19 

SP"^a'ene-2-carboxvlicac»d methviesterj 



EXAMPLE 20 




31 



EP0 661 259 A1 

To a solution of compound XVIa (i S7 mn n 7<> 
nylmagneslum bromWo (3.0 M MhTtL L^^^ J!!^ (5 ""L) at-78-C «ras addad nh«. 

atur. (2 hours), the readlon mSu^^^J^!^ '•Jl'™"'"' '"'-)• ^f^r ^^ing^^^^!^ 

» J=8.3. 2.0 Hz. 1HJ. 7.85 (d. J=2.0 Hz 1H) 750 ?h i A ^ '""NMR (CDCW- 8 7 95 f*l 

EXAMPLE 21 

g-5^""ethvt.5.<^.h^H^.„henyl.n,pH>K..^- ^ 



18 



20 



25 




?r • ' "n S^^^^^^^ -action n,ixtu« was coCed'^t^^ 

mmol. 0.74mL) at room temperature After 2 ^ ^ ^ ""-^ ^"^ '^^ated with 10 N l^aOH f7 s 

•We conected by vacuum f .Iteration togl^^l J^g a^;:^^.^ '"'-> ^«'^«<' and S e p^'^' 

(dd, J=2.0, 8.5 Hz. 1H). 7.75 (d. J=2 0 Hz IH^Ay /T^^o j 1""^ compound; 'H-NMR (DlWSO-dJ- 8 79S 
2.40 (d. J=4.e Hz. 2H). 1.40 (i *?sToc71;^f ^^^^^^^^ ' ^H)- 6 05 {, J.^e't' Jj^' 

EXAMPLE 22 



30 



»lcarbonyl]aminQ|benzoic add, mp^ hyl ester ( Paj 



35 



40 



45 




A solution of compound XVIIIa ri'^i; m/« n .io« 
thylformamide was aiiled ^Jr^^'^'^Tti '^^V'^'-'oride (5 mL) with 2 d„.ps of N.N-dime- 
Z^^l 'T"*'"'*^ ^ reZ^eZTsJ.ll Tll,L'^ homogeneous win 1 W and 

meth/ 4-aminobenzoate (Aldrich, 0.534 mmorsi maTi^lTh "^"'"^ """J was added 

diluted with IN HCI. extracted with ethyl aSe < 00 if k * """^ '^'"P^rature. the mixture was 
salted sodium bicart.onate (2 x 100 m J iJe <^r„t^' ^^C' ^ « ^L) and w^d ^Jh 

J-7.0 Hz. 2H). 7.75 (m, 2H). 7.65 fd J=7 0 9m , c« , * compound; iH-NMR (CDaj- fi 8 05 M 

3H). 2.45 (d. .=4.6 HZ.1H, l'4?;s"; i^y!^^^'-^:^^^;' ^ ^'^^ "m-S 

EXAMPLE 23 



H(S.6-Dihyd,o.5.5.dimethvl-a-nh.n^.,,„.r-nlrn| 



55 



)carbonyllamrno]benzotc arJrt fi4o| 



32 



EP 0 661 259 A1 




10 



IS 



20 



25 



mU 1.65 mlllS atmlTt^^ «8 -"9) ethanol (5 mL) was added ION NaOH i iRi; 

EXAMPLE 24 * ' ' ' «2. 



30 




■OCH, 



.490mg(2.1lmmol)ofcoi!>. 



EXAMPLE 25 



40 



45 




SO 



ss 



.95 
.6 



EXAMPLE 26 



33 



EP 0 661 259 A1 




XT 



10 



IS 




EXAMPLE 27 



20 



dro-5,S-dimethv 



jlamino^benzoic acid (Hb) 



25 



30 



35 



40 




. ^^.01. H. 6.80. N. 3.86. Found: C. 72.84; H. 6.61; N, 3.86 

EXAMPLE 28 



8>Hydraxv-S.5 fi-trimethyl.5 ft 7 



onaphthalene.?-carfaoxylicaniH m^^Ky 



ester ( 



45 



50 




OCH, 



55 EXAMPLE 29 

L6-D'hydn^5,5,8-trimethvlnathth.i.n^o_..^. „ . , 



/Illc) 



34 



EP0 6612S9A1 




10 



15 



Using a method analogous to the preparation of the S-nh, 
pound JC^gave 154 mg (Y: 94%) of the^e ' 



EXAMPLE 30 



6H). 



[(5.6-DihvdrD-5.5,8-trfmethyl-3-nanhfK^,^n 



)carbonvl|aminQ|ben20ic acid, methvt ester mr,\ 



20 



28 



30 





EXAMPLE 31 



40 




45 



50 



55 



NMR: 166.93. 166.13. 1^8.2 Sm^Lm'S^I^^^ <'<B0: 2958. 1674. 165^^^^^ 

Anal. calcd for C2,Hj,N,0,:C 7520- H fiti MT'* r 

,u,. c. 75.20: H. 6.31; N, 4.1. Found C. 74.90; H. 6.36; N. 3.99 

EXAMPLE 32 



dg.6-Dlhydro-5,5-dlmethvl^nh.ny..„,r..«-., ^ 



35 



EP0 661 259 A1 



10 



18 




EXAMPLE 33 



28 



35 



40 



48 




!^1-pronenyllben2o?cacid. ethyl 



COjCH^ 



EXAMPLE 34 



•(5,6^ihYdro-5,S-dimethw 



IJbenzoic acid (lea) 



88 




-COjH 



36 



EP0 661 259 A1 

nol to provide 60 mq (Y- 4n%\ »k-. 
EXAMPLE 35 



10 



IS 



20 



28 




To a solution of compound XIV ^2 on « m c 

butyjdimethylsilyl Chloride a T'^ <«methylformamlde (16 mL) was added 

5 hours 5%Naunn .\ ^ mmoi) and imidazole M 79 n 9a ^ » ^ aaaed tert- 

EXAMPLE 36 



40 



45 



f^-dihydro^5.S^8».ethyl-a.triflMnr^^..u. 



lanesulfonylnanhfhot^^f^ . 




To a solution of compound XXIa /3 7? « p no 

0.«8 (s. 9H). 0.20 (s. 6H,; MS (DcV^e: (i^T ' '"^^ ''^^ ^^ ^t l S 

EXAMPLE 37 




37 



EP0 661 259 A1 



10 



15 



20 



25 



SO 




To a solution Of compound XXMa ?ft n cio 
perature was added trlphenyla^/300 n^' o ilT^ ^ 1^ ^''"^^^'y-^.pynolidinone (25.0 mL) at loom 
^9; 0.16 nimol), and trfbutylphen;^^^^^^^^ J™^^' tris(dibenzyfideneaceloni dfpidj^^ 

andethylacetate(50mL)werLdTH TK ^' ^"^ After stirring at 85X for 16 h«i« !T 



EXAMPLE 38 




35 



40 



45 



To a solution of compound XXMIa i in 
EXAMPLE 39 

Di-tert-butyi ter ephthalate ( vvx/i^ 



50 



55 



.J^V St" 10 ' *y warn. o» n ™ , 



38 



EP0 661 259 A1 



EXAMPLE 40 



Mono-tert-bufyl f erephthalate ( vvx/..^ 



10 



IS 




COH 

MS (DC, 22§ (mS^" "''^^ <^ «,e title co^pou™* iH-NMR (C^C^i 
EXAMPLE 41 



20 



28 



Qbenzoic add. teit-buK 




40 



45 



To a solution of compound XWii /m? 
EXAMPLE 42 




50 



55 




COjH 



I ""-^WM added. The precipitate was collected 



39 



10 



0 661 259 A1 

byvacuumfiltration. washed with IN ur-i . . 

(CDCy: 6 13.39 (bs ih) \~-!fh ^ ""^^ to flive 85 mg (Y- 71%) of .k^ 

6-73 (8. IH). 6.06 (t. j3:2 i , l^J « C*. J=^6 Hz. 2H i 7 3^^!, fijf WIe «^po„„d. 
148.51. 142 55 13Q 77i,T: ^* ''=*-2 Hz. 2H). 1 32 ?s 6H». ilr V^i^' Hz, IH), 

127.63 127 4?\2f27;''!;^'f«''- 132.45. 13 fl^loil^.T^^''^^^^^ 1^3.99. 

. /^o.o». M, 5.69. Found: C. 76.68: H. 5 89 

EXAMPLE 43 



j^aggiyybenzol c add tert-buty t e^«, (v>^.„„^ 



18 



20 



30 



HO 
EXAMPLE 44 

f-IKS.6-Dlhyrtm .5.5^ln,e,^^ „ 




carbonate (2x 100^l? th ^' (4 x 100 mLVlnT HC «- 

EXAMPLE 45 ^ ' ^® "^^^ ^55 (MH*). ^ 



bgjgghthalenvl)carbnny,. ^jb,^^.^ add 



40 



EP0 661 259 A1 



5 




10 



15 



20 



To a sofution of compound |fla i9n^ 

^ • ^' ^5.47; H 5.77. Found: C. 75.52; K 5.43. 

EXAMPLE 46 
5,S.Dtniethy 

^ -■-••--"'■■T-mna,nrnnlnn e.2-carbo3odjo_ac[d^^ 



drox 



fc_5>6.7,e-tetfahyWronaththalAna.O-..rt,^^ 



2ff 



40 



45 




'OCH3 



To a solution of compound XVIa f297 ^ 00 



EXAMPLE 47 



5D 



55 




EPOSei 259 A1 



(m,eH).6.09ftJ^.5Hz.1H).2.38(d.J^ 
EXAMPLE 48 



5 Hz. 2H). 1.32 (8. eH); MS (DCI) m/e 297 (MH^ 



10 



18 




20 



25 



was then allowed to stir af . ^ "^"P^ N.N-<limethvlf«»mrr^ '""■^ 'seated 

BCAMPLE49 ' '-^-^ ^'^^ (DCo'Se;?^^^^:"^"^^ 
i-mS.6-Dlhydm..S'>.dimethy..«.p,n..,.^^^ , 



40 




<5 



MS (DCI) m/e: 416 (MH*) ^' ^^ ^S. 33.48. 

'R(KBr): 2962, 1688. 1594. 1520 

Anal. ca,cd.forC«H,N,O.F,. 0.25 H,ac. 74.36; H. 5.40- N 334 . . 

EXAMPLE 50 ^' ''-5°= N. 3.17 

5>S-Dimeth 



42 



EP 0661 259 A1 




COOMe 



10 



15 



20 



40 



45 



nwnoO was added and »h««l ^•'^'*'**'^'"9fo'16 hours addih«nJ! n^- °' acetonltrile 

Of calite. and Chi 12 ^ for 16 hours Silt'^ (^-OSs. <75 

water (30 rCd^JlSl^"*^""'''''- '"'^ collected was e^o^t^f "1'^" """'^ "^'"^^ « P^d 

EXAMPLE 51 

o 

extracts were dried over m«nl„ • extracted with ether m 1^ 'wth saturated 

pound as a soJi^S •■ 

2.55 (dd. J - 9 3 17 s T i * ^ J = 6.9 Hr. 3 H) 1 30 7L / ^'^"^^ ««« «>m- 

A-.c.cd..rc.xsfcr7?iirH;?.?^;^^^^^ 

EXAMPLE 52 



SO 



$0 



55 







acjd, methyl fiisfAr/ 



<lla) 



Ph 



43 



to 



15 



EP 0 661 259 A1 

over magnesium sulfete f lite^T^i ^« combined extracts w« ^ ammonium chlor- 

P-toluensulfonic aS£ i'^'^ f^''«^^^^ 

was purified by ^Z^J*^ ^l.Tred at reflux l^lSn^Z?^'^''"*^'^^ """z*"" and 

(78% yield) Of SI. °" ael (eluted eSL «^«P<^ated. The residue 

1 H). 7.69 (d. J « 1 8 te' 1 M • T ^ W- J ■ 5.0 Hz 1 H» 7 « 7 7 ^ "J' "••29. 1-36 (s. 



EXAMPLE 53 

P"^"^-^-*^^-^--frnn-iphllMl ,„ 



2ff 



30 



35 



A solution of compound XXXii 

rrrnraSfi--^^^ 

washed With water (1 0 mS dned E^Ac (S^nJ x^'C"*^"'"'' '"«'«^ ""uced 

(<*. J = 7.1 Hz. 3 H) 1 31 1 -ir Z^V^ P™""* (Quantative viald) tTTrL ^"'"^ "^^^ crystal- 

7-46 (d. J = 8 1 Hz 1 H, 7 73 f " 2-35-2.45 (m. 1 ^.TssTd i - . iT' ^^^D^^O « 

EXAMPLE 54 »i-M.H.8.8e. 

^'^^'^^^^''^^^ . 

g^'^"'^'"-""?'^ ir irl ,l, methyl ^ar^ ,3^j 



■COOMe 




55 



a-um sulfate, filtered and eSSl?l^'°^ '^0 mL X 3). The combineStSSt! diluted 
With hexane : EtOAc 101 ZTT^^ '^'""^ """^ P"""^^ by S Ij^if "^"^ '"^ane- 
6 1.03 (d. J = 7.1 Hz 3 H T^n l^^r (^8% yield)of the til f«lZr 9el (eluted 

1.8. 8.1 Hz, 1 H) 7 97 anrt fl nn / ^* ''^^ ^ * 1-8 Hz 1 Hi 7 L . Hz. 1 H) 

A"a..Ca,cd.forUCrJrc:^;:3V^^^^^ 

EXAMPLE 55 ' ' N. 3.33. 

4-g(5.6.DlhYdm.i;i:c.rf . 



EPOeei 259 A1 




COOH 



10 



IS 



'H-NMR (DMSo2 iT^oV « r* S'^^ ^27 mg (59% yieTof 3. !P ^'^'^^ '"^'ed. 

Ana,.Ca.cd.fcrcW»NO,.0.5^^..C ^^.72 (s. 1 H, MS 

HXAMPLESe 77.41.. H. 6.05; N. 3^. 



EXAMPLE 56 



25 



30 



35 



40 



45 



£±carfaoxy|fe acid, m^fhy, ..^^^J 

O 

strring for2 hours th« cn7'r ^-^l ""L. 2.71 mmol) at -^octlw ^ WsPH- 

•ure was extracted with EtJ^ (^"iTfaS "'"kT'^'' 

and evaporated The tpqw..^ x and the comb ned extract* u/ar^ <4 • ^ "^L). The mix- 

EXAMPLE 57 



COOMe 




55 



To a solution of ketone XXXVa (son 

(25 mLx 3) ThTLrM "'"'^'^^ ammonium chloride solution fM mTf^^ « " 'C for 1 

added be tie (1^tt^ra„r?f' ^''•^ '•^^^ 

-.1.0,to..e3ao..c^.^S^?rC»^^^ 

45 • • 3 H), 



EP0661 259 A1 

EXAMPLE 58 



MS 




10 



IS 



20 



Ph 

Asolution of ester XXXVIaMftOm^ nen 
were washed wHh water n^I? I "^^^ ^^'^^ted with EtoS ^ mL under 

^ • H, 6.96. Found: C. 81.01; H. 6.82. 

EXAMPLE 59 



u'nolbenzoic ariri met^y, ^,3^^ 



30 



5 




To a solution of acid XVHIf M71 m/i n c« 
EXAMPLE 60 



COOH 



46 



HP 0 661 259 A1 

EXAMPLE 61 ' 3.27. 



« EXAMPLE 61 



f5 



20 




!ro^mhfacen^9,carboxvffe «wh 



COOMe 



methyl ester (yywii^) 



25 



30 



Asofution of enone XXXa ( son 

was evaporated and t^lr * saturated sodium chloride and drilT «"«Wned extracts 

H each), lio-?./? ri ll'^tSSt' "'^"^ roT^Sl)^^^^ 

5.53-5.58 (m. i h) T^tis^;!, ; ^ 2-99-3.06 (bd Tb i « ^-^S. 1.49 (s. 3 

EXAMPLE 62 



" *=^xy>i c acid, methyl A«fm. /vv^^|„^> 




47 



EP 0 861 259 A1 



10 



18 



20 




HO. extracted w/mEWAc (30 J 

magnesium sulfate. niteredinH ^' «*"Wned extracts were *a!h.H ^ ^^^^ ^'^ 1 N 

^ ' ' «3 Found: C, 83.25; H. 6.86. 

EXAMPLE 64 



garbonvnaminnw.^:, ^^.^ ^^^^ 




30 



35 



40 



4S 



55 



To the solution of acid XVflla ^225 mA n eo 

sW"e was aided 15 ''""L^" ^^-Po-^ted an^rhfir ° °^ '0^2 lur^^d 

1 N HQ (20 n,L) and eX^Id wiS^p.n^""'''- "^^ was evaporatedl^HT*^* r*"*" 

sutfete. nttered/and eCr^^ed I'S^iL'l^^ ^ "«t^^^^^^^^^ "'""^ 

hexane ; EtOAc 20-1 m 7 . '^'^^ Purified by flash rhm„. J f "laganeslum 

*5d2aOa:Iet«h^d^^ 

Daminolben yoic acid (|4f^ 
O ^^^COOH 



Asoiutionofester|3f(210mo n^c 




EP0 661 259 A1 



10 



IS 



20 



25 



rated. The residue was purified h 

A"a..Caicd.forcXNO.0.r5H,O:C.7781 „ e^O M , ^0-35(s. t H,;MS 

EXAMPLE66 " --—^ N. 3.02. Fou^f c. 76.09; H. 5.99; N. 3.14. 

sodium nilrfte (0.767??; mlS^ ' «>y the dZJSTr^ r " *>y of an 

my. After sbndtng for 30 m(nZ tSlt^ Polassfum iodide Si I '^^terst/mngfbr 15 

Phase was then concentralldT': S"*" extracted with ^hvtSfl^'/^ "^^r (18.8 

acetate in hexane) to^ 1 1 " ^ " "^"^ ^'o-^aCpTed ° "^^ "^an/c 

Wd. J=8.3. 2.0 Hz 1H? rV;^ "'''^ tt'e Praduct i|W MA^ ^^nX . (eluted with 5% ethvl 

(DC) n.e: 301 ^i^' ^'^^ ''-^-^ 1H). Z72 (t! ^=«-?H^2r2!5l7^^^^^^^^ 



EXAMPLE 67 



30 



35 



40 



45 




acetate(l00n,g^aTSrK"'*.*''' •'^^'^^^ 

was then separa,raStn^„^' ^"'^ ^ "H^"^ 3 h'elhy 
5% ethyl acetate InhTa^^^TV' "^^ ««Wue w^^^^'^ '^ne(50n,L). The organic ph^ 

2H). 7.47 (d. J-8.rHrSS i 7«? 'f^' ^•^)^^^ title p^^r^M^p^^"' °" ^ ^ 

1H).3.91(s.3H);MS 

EXAMPLE 68 



L"yl]benzolc arJH nwthW e.<»ter fv. 




or4 1, and then allowed to stirat room tern- 



EP0 661 259 A1 



EXAMPLE 69 ^" f^^') "^^^ (MfT), 



10 



18 



20 




EXAMPLE 70 




To a solution of compound XUa m •»« « , .... 
de): 8 12.87 fs 1 HI 7 bi;^ 7 filtration to give 1 .23 g fy- 97%) „f ,«L "° mL) was added 

. cj^.b8. H, 6.50. Found: C, 83.00; H, 6 41 

EXAMPLE 71 



[Isulfamyllbenzoic acid (li2a) 



50 



EP 0 661 259 A1 



10 



15 



20 



2S 




^ • ' 5.64. Found: C. 71.65. H. 5.44. 

EXAMPLE 72 

l-irf(5.6.7.8.Tfi»r ^K 
(XUVaj 




estBr 



50 



40 




oiganlc phase was tLnssn^ m H*-^ saturate^solm ^'^^ «°«'at« 



butyl ester ( ViVa^ 



t- 



51 



EP0 661 259 A1 



5 




Using the method for the preparation of the a-phenyl derivative XVIIa. 80 mg (0.19 mmol) of compound 
XLIVa gave 46 mg (Y: 50%) of the title product; ^H-NMR (COaa): 6 8.03 (m, 4H). 7.52 (d. J=8 2 Hz 1 H) 7 43 

EXAMPLE 74 



^•tI[(5.6-D}hyd ro-5,5-dimethyi-8-phenyi)-2>naphthalenvqsulfamyllcart)onyll^ acid (M^a) 



20 



25 




30 



3S 



To a solution of compound XLVa (46 mg, 0,094 mmol) In toluene (5.0 mL) was added a few miiligrams 
3 mg) of p-toluenesulfonic acid. After being heated at 70»C for 0.5 h. the reaction mixture was cooled and con- 
centrated in vacuo. The residue was then dissolved in methylene chloride (2.0 mL) to which was added tri- 
fluoroacetic acid (0.08 mL) at room temperature. After 16 hours, the reaction mixture was diluted with ethyl 
acetate (20 mL) and washed with 1N HCI (20 mL). The organic phase was separated, dried over anhydrous 
magnesium sulfate and concentrated in vacuo to give 34 mg (Y: 87%) of the title product; ^H-NMR (DMSO- 
de) : 6 8.03 (m. 4H), 7.53 (d. J=8.1 Hz. 1H). 7.43-7.30 (m. 6H). 6.96 (d, J=1.9 Hz, 1H). 6 07 (t J=4 5 Hz 1H) 
2.36 (d. J=4.5 Hz. 2H), 1.18 (s. 6H); MS (DCI) m/e: 415 (MH*). IR (KBr): 3432, 2962. 1680 1202 - ' ' 
Anal, calcd. for C2»H22O3Si.0.35 HjO: C. 74.21; H. 5.44. Found: C, 74.18, H. 5.22. 

EXAMPLE 75 

4-g(5.6-Dihydro-5.5-dime thyt-.8-phenyt)-2-naphthalenyl]ethyl]ben2oic acid, ethyl ester 



45 



SO 




ss 



To a stirred solution of compound psg (lis mg. 0.290 mmol) In toluene (7.0 mL) was added 5% palladium 
on calcium carbonate, poisoned with lead (Aldrich. Lindlar catalyst, 15 mg) at 45 psi of H2. After 16 h the re- 
action mixture was filtered through a pad of celite and the filtrate concentrated in vacuo to give 60 mg (Y- 50%) 
of the title compound; ^H-NMR (CDCI3): 5 7.93 (d, J=8.1 Hz. 2H). 7.30 (m, 6H). 7.18 (d. J=8.1 Hz. 2H) 7 05 



52 



EP0 661 259 A1 



(dd. J=7.9, 1.8 Hz, 1H). 6.81 (d. J=1.8 Hz. 1H), 6.97 (t. JM.5 Hz. 1H), 4.38 (q. J=7.1 Hz. 2H). ^84 (m, 4H). 
2.34 (d, J=4.5 Hz. 2H). 1.42 (t, J=7.1 Hz, 3H). 1.33 (s, 6H); MS (DCI) m/e: 411 (MH*). 

EXAMPLE 76 



4-[I(5,6-Dihydro-5,5-dimethyl>6-phenyi)-2-naphthalenyllethyl]befizoic acid (P^a) 



10 



18 




To a solution of compound 4-ir(5,6-dihydro-5.5-dimethy|.8-phenyl)-2-naphthaIenyl]ethyl]benzoic acid, 
ethyl ester (60mg. 0.146 mmol) in ethyl alcohol (5.0 mL) was added 10 N NaOH (2.0 mmol. 0.20 mL). After 1h 
20 at 70«C an excess of 1 N HCI (20 mL) was added and the precipitate collected by vacuum filtration to give 59 
mg (Y: 99%) of the title product; ^H-NMR (DMSO-de); S 7.79 (d. J=8.2 Hz. 2H). 7.38-7.29 (m, 3H). 7.25 (d. J=8.2 
Hz, 2H). 7.21 -7.1 0 (m. 4H). 6.82 (d, J=1 .7 Hz, 1 H). 5.93 (t. J=4.5 Hz, 1 H), 2.78 (m, 4H). 2.25 (d, J=4.5 Hz. 2H). 
1.24 (s. 6H). MS (DCI) m/e: 383 (MH*); IR (KBr): 2956, 1688. 1610, 1422 m-\ 
Anal, calcd. CjzHzeOa: C. 84.78; H, 6.85. Found: C, 84.53; H, 6.81. 

28 

EXAMPLE 77 

4-[[[(5.6-Dlhydro-5.&-dimethyl>8-phenyl)-2-naphthalenyl]thlocart)onyllamlno]benzoic acid, methyl ester 



35 




40 To a solution of compound l^a (285 mg, 0.693 mmol) in telrahydrofuran (6.0 mL) was added phosphorus 
pentasulf Ida (Aldrlch, 205 mg, 0.461 mmol). After 0.75 h at reflux, the mixture was concentrated down, diluted 
with methylene chloride (50 mL) and washed with 5% sodium carbonate (2 x 50 mL). The organic phase was 
then concentrated in vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in 
hexane) to give 88 mg (Y: 30%) of the title product; iH-NMR (CDCI3): 5 8.92 (s. 1H), 8.05 (d, J=8.6 Hz. 2H), 

45 7J4 (dd. J=8.2. 1.8 Hz. 1H). 7.43 (d. J=8.1 Hz. 1H). 7.33 (m. 8H). 6.07 (t, J=4.5 Hz. 1H). 3.92 (s, 3H). 2.38 (d! 
J=4.5 Hz, 2H). 1.36 (s. 6H); MS (DCI) m/e: 428 (MH^. 

EXAMPLE 78 

^ ^-[[H5.6-D'hydro-S.5-dimethyl-8-phenyl)»2-naphthalenyqthiocarbonyllamino]benzoi^ acid (M^a) 



53 



EP0 661 259 A1 



5 




Using the method given for the preparation of th e 8-phenyl derivative ha. 80 mg (0.1 86 mmol) of 4-[[[(5.6- 
dihydro-5.5-dimelhy^8-phenyl)-2-naphthalenyIlthiocarbonyf]amlno]benzoic acid, methyl ester gave 69 mg (Y* 
90%)of the title product; 'H-NMR (DMSO-de): 5 12.88 (s. 1H), 11.89 (s, 1H), 7.87 (m. 4H). 7.60 (dd. J=8.0. 1.7 
Hz, 1H). 7.47 (d. J=8.1 Hz. 1H). 7.35 (m. 6H). 6.07 (t J=4.5 Hz, 1H). 2.35 (d, J=4.5 Hz. 2H). 1.32 (s, 6H); MS 
18 (DCI) m/e: 414 (MH^; IR (KBr): 2922. 1688. 1606. 1514 cm-i. 

Anal, calcd. for C^eHiaOaNiSrO.S HjO: C. 73.91; H, 5.73; N. 3.31. Found: C. 73.60; H. 5.76; N. 3.21. 

EXAMPLE 79 



^ 5.6-Dihydro-5. 5-dimethyl-2-ri-(trimethylsilyltoxy]ethenyl-8-phenylnaphthalene (LVIa^ 




To a solution of compound XlXa of EXAMPLE 32 (2.73 g. 9.89 mmol) In anhydrous methylene chloride 
(10.0 mL) was added 1.8-diazabicyclo t5.4.0Jundeo-7-ene (Aldrlch, 1.80 g. 11.87 mmol) and chlorotrimethyl. 
silane (1.18 g. 10.9 mmol). The reactbn mixture is allowed to reflux gently for 2h and stin-ed at room temper- 
ature for 16 h. Pentane (100 mL) Is added to the mixture and the solution is washed with 0.1 N Ha (50 mL) 
35 and dilute sodium bicarbonate (50 mL). The organic phase is then dried over anhydrous magnesium sulfate 
and concentrated in vacuo to give 3.17 g (Y: 92%) ofthe title product; iH-NMR (CDCI3): d 7.45 (dd. J=8 0 2 0 
Hz. 1 H). 7.39-7.24 (m, 7H). 5.99 (t. J=4.5 Hz. 1H). 4.74 (d. J=1.6 Hz. 1 H). 4.30 (d. J=1.6 Hz, 1H). 2.35 (d. jU.5 
Hz. 2H). 1.34 (s. 6H), 0.14 (s, 9H). 

40 EXAMPLE 80 

4'in(5.6-Dihydro-5. 5-dimethyl-8*phenyl-2-naphthalenyllcarbonyl]methytlbenzoic acid, methyl ester (Ra) 



SO 




•CP2CH, 



To a solution of compound LVIa (864 mg. 2.48 mmol) and methyl 4-bromoben2oate (Aldrich. 355 mg. 1.65 
mmol) in anhydrous benzene (10,0 mL) was added tributyltin fluoride (Aldrich. 806 mg. 2.61 mmol) and 
PdCl2(P(o.CH3CeH4)3)2 [(59 mg, 0.074 mmol) made from bls(acetonltrile)palladium (II) chloride (Aldrich. 0.074 
mmol, 19.3 mg) and tri-o-to!ylphosphine (Aldrich. 0.149 mmol, 45.3 mg)J. Af ter4 h at reflux, the reaction mixture 
was diluted with ethyl acetate (50 mL) and washed with IN NaOH (50 mL). The organic phase is then chrx>. 
matographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 265 mg (Y: 39%) of the title product; 



54 



EP0 661 259 A1 



1H-NMR (COaj): 6 7.92 (d. J=8.5 Hz. 2H). 7.87 (dd. J=8^. 2.0 Hz, 1H), 7.83 (d, J=2.0 Hz. 1H). 7.44 (d, J=8.2 
Hz, 1H). 7.41 (m, 3H), 7.29 (m. 2H). 7.17 (d. J=8.0 Hz. 2H). 6.03 ft J=4.5 Hz. 1H). 4.12 (s. 2H). 3.90 (s, 3H). 
2.37 (d, J=4.5 Hz, 2H), 1.35 (s. 6H); MS (DCI) m/e: 411 (MH^. 

EXAMPLE 81 

4-Ig(5.6-Dihydro-5.5-dimethyl-8-phenyl)"2-naphthalenyOcart)onyl]methyllbenzoic add jl^^a) 




To a solution of compound Pa (200 mg. 0.488 mmo!) in anhydrous toluene was added dibutyltin oxide 
(Aldrich, 364 mg. 1.46 mmol). After 16 h at reflux, the reaction mixture was concentrated in vacuo and the re- 
sidue chromatographed on silica gel (eluted with 5% methanol in methylene chloride) to give 70 mg of Impure 
product (tin by-products present), A second purification by preparative thin layer chromatography afforded 10 
mg {Y: 5%) of the title product; ^H-NMR (DMSO-dfl): 6 7.99 (dd, J=7.9. 1.9 Hz, 1H). 7.82 (d, J-8.0 Hz, 2H), 
7.54 (d. J=8.0 Hz. 1H). 7.49 (s. 1H). 7.42 (m, 3H). 6.05 ft J=4.5 Hz. 1H). 4.30 (s. 1H), 4.28 (s. 1H), 2.34 (d, 
J=4.5 Hz, 2H), 1.31 (s. 6H): MS (DCI) m/e: 397 (MH^; High res. M.S. Calcd.: 397.1804. Found: 397.1816, 3.0 
ppM deviation. 

EXAMPLE 82 

5,6-Dihydro-S,S-dimethyl-2-hydroxvmethyl-8-phenylnaphthalene (LVIIa) 




A solution of 95% lithium aluminum hydride powder (LAN. 40 mg, 1.0 mmol) In anhydrous diethyl ether 
(5.0 mL) was allowed to reflux until most of the hydride dissolved. A solution of compound XVIIla (485 mg, 1 .66 
mmol) in anhydrous diethyl ether (5.0 ml) was then slowly added. After 0.5 h. ethyl acetate (20 mL) and 1 N 
hydrochloric acid (20 mL) were added. The organic phase was separated, dried over anhydrous magnesium 
sul^te and concentrated in vacuo to give 368 mg (Y: 84%) of the title compound; ^H-NMR (CDCI3): 5 7.36 (m, 
6H). 7.26 (m. 1H). 7.02 (d. J=1.8 Hz. 1H). 5.99 ft J=4.5 Hz. 1H), 4.55 (s. 2H). 2.05 (d. J=4.5 Hz. 2H). 1.34 (s. 
6H); MS (DCI) m/e; 247 (M-'-OH). 

EXAMPLE 83 

5,6-Dihydro-5,S-dimethyl>2-bronriomethyl-8-phenylnaphtha[ene (LVIIIa) 



55 



EP0 661 259 A1 




To a solution of carbon tetrabromide (Aldrich. 1.36g, 4.09 mmol) and triphenylphosphine (Aldrich, 1.07g. 
4.09 mmol) in anhydrous diethyl ether (20 mL) was added compound LVIIa (900 mg, 3.41 mmol). After 16 h at 
room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue 
was chromatographed on silica gel (eluted with 3% ethyl acetate in hexane) to give 790 mg (Y: 71%) of the 
title product; 'H-NMR (CDCI,): fi 7.39 (m. 6H). 7.27 (dd, J=8.1, 1.8 Hz, 1H). 7.04 (d. J=1.8 Hz, 1H). 6.01 (t. 
J=4.5 Hz. 1H). 4.39 (S, 2H). 2.35 (d, J=4.5 Hz. 2H). 1.34 (s, 6H); MS (DCI) m/e: 327 (MH*). 

EXAMPLE 84 

4-I[[(5,6-Dlhydro-5,5-dimethyl>8-phenyl)-2-naphthalenynmethyi]oxy]benzoic acid, ethyl ester Q^^a) 




To a solution of ethyl 4.hydroxybenzoate (Aldrich. 152 mg. 0.917 mmol) In ethylene glycol dimethy ether 
(6.0 mL) was added 60% sodium hydride (1 .05 mmol. 43 mg) at room temperature. After 0. 1 5 h. compond LVllla 
(330 mg, 1.01 mmol) was added. After 16 h the reaction mixture was diluted with ethyl acetate (50 mL) and 
washed with 1 N hydrochloric acid (2 x 50 ml). The organic phase was concentrated in vacuo and the residue 
chromatographed on silica gel (eluted with 10% ethyl acetate in hexane) to give 64 mg (Y: 17%) of the title 
product; ^H-NMR (CDaj: 5 7.97 (d. J=8.8 Hz. 2H). 7.36 (m. 7H). 7.06 (s, 1H), 6.92 (d. J=8.8 Hz. 2H). 6.01 (t. 
J=4.5 Hz. 1H). 4.96 (s. 2H). 4.34 (q. J=7.2 Hz, 2H). 2.36 (d. J=4.5 Hz. 2H). 1.40 (t. J=7.2 Hz, 3H) , 1.35 (s, 6H); 
MS (DCI) m/e 413 (MH*). 

EXAMPLE 85 

4»[Tr(5.6-Plhydro-5.5-dlmethyl-8-phenyl)-2-naphthalenynmethvl]oxy]benzolc acid (P^a) 




Using the method given for the preparation of the 8-phenyl derivative l-'a. 64 mg (0.155 mmol) of compound 
|2«a gave 50 mg (Y: 84%) of the title product; ^H-NMR (DMSO-de): 6 12.59 (s, 1H), 7.83 (d. J=8.8 Hz. 2H). 7.33 
(m, 7H), 6.97 (d. J=8.9 Hz. 2H), 6.96 (s. 1H), 5.99 (t. J=4.5 Hz. 1H), 5.04 (s, 2H). 2.30 (d, J=4.5 Hz, 2H), 1.27 
(s, 6H); MS (DCI) mie: 385 (MH") ; IR (KBr): 2958, 1682. 1604. 1252 cm-\ 
Anal, calod. for C26Ha4O3 0.25 HjO; C. 80.28; H. 6.35. Found: C. 80.41; H. 6.23. 



56 



EP0 661 25dA1 

EXAMPLE 86 

4-[[[(5.6«Dlhydro-5.Mimethyl-8-phenyl)-2'naphthalenyOoxylfne^ 




To a solution of compound XXVa OF EXAMPLE 38 (1 93 mg. 0.772 mmol) In ethylene glycol dimethyl ether 
(5.0 mL) was added 60% sodium hydride (36 mg, 0.888 mmol) at room temperature. Methyl 4-(bromome- 
IhyDbenzoate (Aldrlch. 1 95 mg. 0.848 mmol) was added after 1 5 minutes. After 1 6 h at room temperature, 60% 
sodium hydride (36 mg. 0.888 mmol) was added again. After 24 h. at reflux, the reaction mixture was diluted 
with ethyl acetate (50 mL) and washed with 1 N hydrochloric add (2 x 50 mL). The organic phase was con- 
centrated in vacuo and the residue chromatographed on silica gel (eluted with 5% methanol in methylene chlor- 
ide) to give 170 mg of impure material. The crude material was dissolved in ethyl alcohol (3 mL) and 1N hy- 
drochloric acid (20 mL) was added. The precipitate was collected by vacuum filtration. 50 mg (Y: 16%) of the 
title productwas isolated; ^H-NMR (DMSO-de): S 12.95 (s. 1H). 7.89 (d,J=8.3 Hz. 2H), 7.42 (d, J=8.3 Hz, 2H), 
7.39-7.21 (m. 6H), 6.88 (dd, J=8.5,2.7 Hz, 1H), 6.44 (d. J=2.7 Hz, 1H). 5.97 (t. J=4.5 Hz. 1H), 5.04 (s, 2H), 
2.27 (d. J=4.5 Hz, 2H), 1.24 (s, 6H); MS (DCI) m/e: 385 (MH^; IR (KBr): 3442. 1682. 1282 arr\ 
Anal, calcd. for C26H24O3 O.5 H2O: C, 80.59; H. 6.50. Found: C, 80.31; H, 6.26. 

EXAMPLE 87 

5,5-Dimethyl-8-hydrDxy-8-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrD>naphthalene-2-carboxylic acid, methyl es- 
ter (XVIIe) 




Using the method given for the preparation of the 8-(2-f luorophenyl) derivative XVIId. 311 mg (1.34 mmol) 
of compound XVIa gave 284 mg (Y: 63%) of the title compound; ^H-NMR (CDCI3): 5 7.91 (dd, J=8.3, 1.8 Hz, 
1H), 7.66 (s, 1H), 7.49 (d. J=8.3 Hz, 2H). 7.02 (d,J=8.0 Hz, 1H), 6.93 (s, 1H), 3.80 (s, 3H), 2.76 (m, 1H), 2.34 
(m. 1H). 2.32 (s, 3H), 2.08 (m, 1H). 1.63 (m, 1H). 1.55 (s. 3H), 1.42 (s. 3H), 1.35 (s. 3H); MS (DCI) m/e: 339 
(MH*). 

EXAMPLE 88 

5,5-Dimethyl-5,6-dihydro-8-(2,4-dimethylphenyl)naphthalene-2-carfaoxylic add (XVIIIh) 




57 



EP0 661 259 A1 



Using the method given for the preparation of 8-phenyl derivative XVIIIe. 311 mg (1.34 mmol) of compound 
XVIIa gave 285 mg (Y: 63%) of the title product; 'H-NMR (CDaj; 5 7.78 (dd, J=8.0, 1.7 Hz. 1H). 7.48 (d, J=8.0 
Hz. 1H), 7.18 (d. J=1.6 Hz, 1H). 7.06 (m, 3H), 5.86 (t J=4.5 Hz. 1H), 2.35 (m, 2H). 2.33 (s, 3H). 1.99 (S. 3H), 
1.39 (s, 3H), 1.28 (s. 3H); MS (DCI) m/e: 307 (MH*). 

EXAMPLE 69 



4-m5,6>D ih ^^ acid, methyl 



15 




Using the method given for the preparation of the &-(2-fluorophenyl) derivative l^g, 221 mg (0.722 mmol) 
of compound XVIIIh gave 67 mg (Y: 21%) of the title product; 'H-NMR (CDCIj): 8 8.00 (d, J=8.7 Hz, 2H), 7.77 
(s. 1H). 7.68 (dd, J=8.2. 1.7 Hz. 1H), 7.63 (d. J=8.7 Hz. 2H), 7.47 (d. J=8.0 Hz. 1H). 7.15 (d. J=1.7 Hz. 1H) 
7.06 (m, 3H), 5.93 (t. J=4.5 Hz. 1H). 3.90 (s. 3H), 2.43 (m. 2H). 2.36 (s. 3H). 2.08 (s. 3H). 1.45 (s. 3H); MS 
(Da) m/e: 440 (MH*). 

EXAMPLE 90 

4-{HI5.6-Dlhy dro-5.5-dlmethyl-8^2.4-dimethylphenyl)]>2>naphthalenyl]carfaonyl]amino3benzoi acid (i*h) 



35 




Using the method gh^en for the preparation of the S-phenyl derivative l^a. 67 mg (0. 1 53 mmol) of compound 
40 |3h gave 61 mg (Y: 94%) of the title product; 'H-NMR (DMSO-de): 8 12.72 (s. 1H), 10.40 (s, 1H), 7 87 (d J=8 8 
Hz. 2H). 7.80 (m. 3H). 7.52 (d. J=8.0 Hz, 1H).7.04 (m, 4H), 5.88 (t, J=4.5 Hz, 1H), 2.38 (m. 2H). 2^1 (s, 3H), 
1.99 (s. 3H). 1.41 (s. 3H). 1.29 (s, 3H); MS (DCI) m/e: 426 (MH^; IR (KBr): 2960. 1688, 1594. 1518 cnr'. 
Anal, calcd. for C28H27N,O3 0.5 H2O: C. 77.39; H, 6.50; N, 3.22. Found: C, 77.57; H. 6.50; N, 3.22. 

45 EXAMPLE 91 

5,5-Dimethyl-8>hydroxy- (4-methylphenvl)-5,6.7.8-tetrahydro-naphthalene-2^rbQxvlic acid, methyl ester 



55 




58 



EP0 661 259 A1 



Using the method g iven for the preparation of the 8-(2-f luorophenyl) derivative XVIId, 260 mg (1 .1 2 mmol) 
of compound XVIa gave 189 mg (Y: 52%) of the title product; 'H-NMR (CDCI3): 6 7.92 (dd, J=8.4, 1 .7 Hz, 1H), 
7.84 (d. J=1.7 Hz, 1H), 7.47 (d. J=8.4 Hz, 1H). 7.10 (s. 4H). 3.82 (s, 3H), 2.34 (s. 3H). 2.18 (m. 2H), 1.80 (m, 
IN). 1.60 (m, 1H). 1.39 (s, 3H), 1.34 (s, 3H): MS (DCI) nVe: 325 (MH^. 

EXAMPLE 92 

5.5-Dlmethyi-5,6-dihydro-8-(4-methytphenyl)naphthalene-2-carl)oxylic add (XVnil) 



Using the method for the preparation of 8-phenyl derivative XVIIIa. 189 mg (0.583 mmol) of compound 
20 XVIIf gave 155 mg (Y: 91%) of the title product; ^H-NMR (CDCI3): 5 7.81 (dd. J=8.0. 1.7 Hz, 1H), 7.51 (d, J=1.7 
Hz, 1H), 7.49 (d. J=8.0 Hz. 1H), 7.23 (m, 4H), 6.00 (t. J=4.5 Hz, 1H). 2.35 (s, 3H). 2.33 (d, J=4.5 Hz, 1H), 1.30 
(s, 6H); MS (DCI) m/e: 293 (MH^. 

EXAMPLE 93 

25 

4-[ni5.6-Dihydro-5,&-dimethyl>8-^4-methylphenyl)l-2-naphthaIenyl]cart)onyl]amino]benzoic acid, methyl ester 



30 



35 




Using the method given for the preparation of the 8-(2-f luorophenyl) derivative l^g, 155 mg (0.531 mmol) 
of compound XVIIIi gave 143 mg (Y: 63%) of the title product 1H-NMR (CDCI3): 6 8.02 (d. J=8.8 Hz. 2H). 7.74 
40 (s. 1H), 7.72 (dd, J=8.0. 1.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.53 (d. J=1.8 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H). 
7.23 (m, 4H). 6.06 (t. J=4.5 Hz. 1H). 3.90 (s. 3H), 2.40 (s. 3H). 2.39 (d. J=4.5 Hz, 2H). 1.54 (s, 3H), 1.37 (s, 
3H); MS (DCI) m/e: 426 (MH^. 

EXAMPLE 94 

45 

4-[I[[5,6-Dihydro-S.5»dimethyl«8-(4-methylphenyl)]-2-naphthalenyl]carbonyllamino]benzoicacid (Hi) 




Using the method given for the preparation of the 8-phenyl derivative l*a. 143 mg (0.336mmol) of com- 
pound m gave 123 mg (Y: 89%) of the title product; iH-NMR (DMSO^«): 5 12.72 (s. 1H), 10.42 (s. 1H), 7.85 



59 



EP0 661 259 A1 



(m, 5H). 7.52 (d. J=8.0 Hz, 1H). 7.44 (d. J=1.8 Hz. 1H). 7.21 (s. 4H). 6.02 (t. J=4.5 Hz. 1H). 2.33 (s, 3H), 2.33 
(d. J=4.5 Hz, 2H). 1.31 (s, 6H): <SC-NMR (DMSO-de): 166.90, 166.06. 148.77, 143.28, 138.16, 136.93. 136.60, 
133.49. 132.48. 130.19, 129.12, 128.21, 126.75, 125.35. 125.03, 123.92, 119.38, 119.29. 37.98. 33.52, 27.75, 
20.79; MS (DCI) m/e: 412 (MH*); IR (KBr): 2960. 1688. 1594, 1518 cm-^ 

Anal, calcd for C2,H25NiO3 0.25 H2O: C. 77.96; H. 6.18, N. 3.37. Found: C. 77.73; H. 6.09; N, 3.29. 
EXAMPLE 95 

4.4-Dlmethyl-7-bromo-1>tetralone (XLVIII) 

To a cooled (10X) stiired solution of sodium nitrate (2.18 g. 13.92 mmol) in concentrated sulfuric acid 
(28.4 mL) and glacial acetic acid (26.27 mL) [prepared by adding sodium nitrate to cooled (1 0**C) concentrated 
sulfuric add, heating to dissolve, recooling and then adding glacial acetic acid] was added a solution of 4.4- 
dimethyl-7-amino-1-tetralone (Xjl) (5.0 g, 26.46 mmol) In glacial acetic acid (89 mL) over 10 mintues. The re- 
sulting solution was added slowly (over 10 minutes) lo a heated (60*C) solution of copper (I) bromide (16.66 
g) In concentrated hydrobromic acid (1 59 mL). The mixture was warmed to 90**C for 10 minutes, cooled, diluted 
with water (250 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were con- 
centrated in vacuo and the residue chromatographed on silica gel (eluted with 3% ethyl acetate In hexane) to 
give 1.95 g (Y; 29%) of the Utie compound; ^H-NMR (CDCy: S 8.13 (d.J=2.3 Hz. 1H), 7.62 (dd. J=8.5, 2.3 Hz, 
1H), 7.31 (d, J=8.5 Hz. 1H), 2.73 (t, J=7.0 Hz, 2H), 2.01 (t. J=7.0 HZ, 2H). 1.38 (s, 6H); MS (DCI) m/e: 253 
(MKT). 

EXAMPLE 96 

4,4-Dimethyl-7-trimethy!silanylethynyl-1-tetralone (IL) 

To a deaerated solution of compound XLVIII (1.53 g. 6.04 mmol). palladium (II) acetate (Aldrich. 15.4 mg, 
0.975 mmol) and triphenylphosphine (31 mg, 0.118 mmol) in anhydrous triethylamine (30 mL) was added (tri- 
methylsllyl)acetylene (Aldrich. 3.0 mL, 21.23 mmol) and heated to lOO^'C over 0.5 h. After 4 h at 100*^0 the 
reaction niixture was cooled to room temperature (16 h). The reaction mixture was then filtered and the filtrate 
concentrated In vacuo. The residue was chromatographed on silica gel (eluted with 3% elhyi acetate in hexane) 
to give 1.24 g (Y: 76%) of the title product; 1H-NMR (COaj: 5 8.11 (d. J=1.8 Hz. 1H). 7.58 (dd, J=8.2. 1.8 Hz, 
1H). 7.36 (d. J=8.2 Hz. 1H), 2.72 (t J=7.0 Hz. 2H), 2.01 (I. J=7.0 Hz, 2H). 1.37 (s, 6H), 0.24 (s, 9H); MS (DCI) 
m/e 271 (MH^. 

EXAMPLE 97 

4.4-Dimethyi-7-ethynyi-14etralone (L) 

To a solution of compound IL (1.24 g. 4.59 mmol). in absolute ethyi alcohol (8.0 mL) was added anhydrous 
potassium carbonate (170 mg. 1.21 mmol) at room temperature. After 2 h the reaction mixture was concen- 
trated in vacuo, diluted with saturated sodium bicarbonte (25 mL) and extracted with methylene chloride (2 x 
25 mL). The organic phases were combined, concentrated In vacuo and the residue chromatographed on silica 
gel (eluted with 5% ethyl acetate In hexane) to give 694 mg (Y: 76%) of the title product; 1H-NMR (CDCI3): 5 
8.15 (d, J=1.9 Hz. 1H). 7.62 (dd.J=8.2, 1.9 Hz. 1H). 7.39 (d, J=8.2 Hz. 1H). 3.07 (s. 1H). 2.73 (t, J=7.0 Hz, 2H), 
2.02 (t, J=7.0 Hz, 2H). 1.39 (s. 6H): MS (DCI) m/e: 199 (MH*). 

EXAMPLE 98 

4-|I(5.6.7,8-Tetrahydro-5.5-dimethyl-8-oxo)-2-naphthalenyl]ethynyl]benzoic acid, ethyl ester (Lla) 




A solution of compound L (153 mg. 0.773 mmol), ethyl 4-lodobenzoate (Lancaster, 160 mg. 0.58 mmol), 
bis(triphenylphosphine) palladium (11) chloride (Aldrich. 923 mg. 0.013 mmol) and copper (1) Iodide (Aldrich, 
4.5 mg, 0.02 mmol) in anhydrous triethylamine (3.0 mL) was allowed to stir at room temperature for 2 h. The 

60 



EP0 661 259 A1 



reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (1 x 25 mL). The organic phase 
was concentrated In vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in 
hexane) to give 183 mg (Y: 91%) of the title product; ^H-NMR (CDCIa): S 8.20 (d, J=1.8 Hz. 1H), 8.04 (d, J=8.3 
Hz, 2H). 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.58 (d, J=8.3 Hz. 2H). 7.44 (d, J=8.2 Hz, 1H). 4.39 (q, J=7.1 Hz, 2H). 
5 2.76 (t, >6.8 Hz, 2H). 2.04 (t. J=6.8 Hz. 2H). 1.41 (t, J=7.1 Hz. 3H). 1.41 (s. 6H); MS (DCI) m/e: 347 (MH*). 

EXAMPLE 99 

4-[I(5,6,7,8-Tetrahydro-5,5-dimethyl-6>phenyl-8-hydroxy)-2'naphthalenyllethynyilbenzolc acid, ethyl ester 
10 (Lila) 



15 




20 

Using the method for the preparation of the 8-phenyl derivative XVIIa. 183 mg (0.529 mmol) of compound 
Lla gave 177 mg (Y: 79%) of the title compound; ^H-NMR (CDCI3): 5 7.98 (d, J=8,3 Hz, 2H). 7.50 (d. J=8.3 Hz. 
2H). 7.47-7.26 (m. 8H). 4.37 (q. J=7.0 Hz. 2H). 2.20 (m. 2H). 1.89 (m. 1H). 1,60 (m. 1H), 1.41 (s. 6H). 1.39 (t 
J=7.0 Hz, 3H); MS (DCI) m/e: 425 (MH^. 

25 

EXAMPLE 100 

4"[I(5,6-Dihydfo-5,5-dimethyi-8-phenyl)-2'naphthalenyl)ethynyllbenzofcacid jV^a) 

30 



35 




To a solution of compound Ula (177 mg. 0.42 mmol) was added a few milligrams (-- 10-20 mg) of p-tol- 
40 uenesulfonic acid. After heating at 70°C for 0.5 h. the reaction mixture was cooled and concentrated in vacuo 

to afford 4-I[(5,6-dihydro-5,5-dimethyl-8-phenyl)-2-naphthaIenyOethynyl]benzoic acid, ethyl ester (P^. The 

residue was then dissolved In ethyl alcohol (5.0 mL) and treated with 10 N NaOH (6.5 mmol. 0.65 mL) at 70"C. 

After 0.6 h, an excess of 1N HQ (20 mL) was added and the precipitate collected by vacuum filtration to give 

142 mg (Y: 90%) of the title product; ^H-NMR (DMSO-de): 6 13.13 (s, 1 H). 7.90 (d. J=8.4 Hz, 2H). 7.58 (d. J=8.4 
45 Hz, 2H). 7.39 (m. 6H). 7.30 (d. J=6.6 Hz. 1H), 6.99 (s. 1H). 6.03 (t J=4.5 Hz, 1H). 2.33 (d. J=4.5 Hz. 2H), 1.29 

(s. 6H); 13C-NIMR (DMSO-de): 166.64. 146.14. 139.79. 137.96. 133,75. 131.50. 130.98. 130.37. 129.48, 128.63. 

128.38. 127.88. 127.60. 127.49. 126.54, 124.69. 119.23. 91.96, 88.11. 37.98, 33.40, 27.75; MS (DCI) m/e: 379 

(MH*); IR (KBr): 2958. 1684. 1604. 1420 cnr\ 

Anal, calcd. for C27H22O2 • 0.15 H2O: C, 85.08; H. 5.90. Found: C. 85.06; H, 5.97. 

SO 

EXAMPLE 101 

4,4-Dimethyl-7-[(dimethyfamino)thiocarbonyloxy]-1-tetralone (XUI) 

To a solution of 4.4-dimethy|.7-hydroxy-1-tetralone (XIV) (3.07 g, 16.16 mmol) in water (10.77 mL) con- 
5$ tainlng potassium hydroxide (904 mg) cooled below 10*»C was added N,N-dimethylthiocarbamoyl chloride (2.67 
g, 21.6 mmol) in tetrahydrofuran (4.30 mL); the reaction temperature kept below 12*'C. After 10 minutes, re- 
action mixture is made basic by the addition of a 10% aqueous KOH solution (5.39 mL). Product is extracted 
with ethyl acetate (2 x 50 mL). organic phases concentrated in vacuo and the residue chromatographed on 



61 



EP0 661 259 A1 



silica gel (eluted with 10% ethyl acetate in hexane) to give 3.74 g (Y: 84%) of title product; ^H-NMR {CDCI3): 
5 7.68 (d, J=2.6 Hz, 1H). 7.45 (d, J=8.5 Hz, 1H). 7.27 (dd. J«8.5, 2.8 Hz, 1H). 3.46 (s. 3H). 3.34 (s, 3H), 2.73 
ft J=6.B Hz. 2H), Z04 ft J=6.8 Hz, 2H). 1.41 (s, 6H): MS (DCI) m/e: 278 (MH*). 

EXAMPLE 102 

4,4-Dimethyl-7-mercapto-1-tetralone(XLIII) 

Compound XLII (3.74 g 13.50 mmol) under nitrogen with a gas outlet was heated at 270-275*0 for 0.75 
h in a salt bath (1:1 mole mixture of potassium nitrate and sodium nitrite). After cooling, potassium hydroxide 
(1.13 g) in water (1.35 mL) and ethylene glycol (10.0 mL) was added to the reaction mixture and it was refhixed 
for 1 h. The cooled reaction mixture was then poured onto ice (30 g). The mixture was washed with methylene 
chloride (2 x 50 mL), made acidic with 1 N HQ and extracted with methylene chloride (2 x 50 mL). The organic 
phase is concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate 
in hexane) to give 1.22 g (Y: 44%) of the title product; 'H-NMR (CDCIa): 6 7.91 (d, J=2.2 Hz. 1H). 7.41 (dd. 
J=8.2. 2.2 Hz, 1H). 7.30 (d. J=8.2 Hz. 1H). 3.48 (s. 1H), 2.71 ft J=6.8 Hz, 2H). 2.00 (t J=6,8 Hz. 2H). 1.37 (s, 
6H); MS (DCI) m/e: 207 (MH*). 

EXAMPLE 103 

4-[[[(5,6,7,8-Tetrahydro-5.5-dimethyl-6-oxo)-2-naphthalenyl]sulfamyOmethvllbenzoic acid, methyl ester 
(XLVia) 



A solution of 4,4-dinr>ethyl-7-mercapto-1-tetralone (XLIII) (262 mg, 1.27 mmol). methyl 4-(bromome- 
thyObenzoate (Aldrlch, 291 mg, 1.27 mmol) and diisopropylethyl amine (Aldrlch. 179 mg. 1.38 mmol) in anhy- 
drous methylene chloride was allowed to stir at room temperature. After 1.5 h the reaction mixture was con- 
centrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to 
give 402 mg (Y: 89%) of the title product; ^H-NMR (CDCI3): 6 7.98 (d, J=2.1 Hz. 1H). 7.95 (d. J=8.5 Hz, 2H). 
7.38 (dd, J=8.3, 2.1 Hz. 1H), 7.38 (d, J=8.5 Hz, 2H). 7.29 (d.J=8.3 Hz, 1 H). 4.17 (s, 2H). 3.90 (s. 3H). Z71 (t. 
J=6.8 Hz, 2H). 1.99 (t, J=6.8 Hz. 2H), 1.36 (s, 6H): MS (DCI) m/e: 356 (MH^. 

EXAMPLE 104 

4-in(5>6,7,e-Tetrahydro-5,5-diniethyl-8-phenyi-8-hydroxy)-2-napthalenyl]sulfanfiyllmethyllbenzoic acid, me- 
thyl ester (XLVIIa) 



Using the method for the preparation of the 8-phenyl derivative XVII a, 400 mg (1.13 mmol) of compound 
XLVia gave 415 mg (Y: 85%) of the title compound; <H-NMR (CDCI3): 6 7.87 (d. J=8.2 Hz. 2H), 7.30-7.18 (m. 
9H). 7.02 (d, J=2.0 Hz. 1H). 3.97 (s, 2H). 3.91 (s, 3H), 2.22-2.08 (m. 3H). 1.85 (m, 1H), 1.36 (s, 3H), 1.28 (s. 
3H); MS (DCI) m/e: 433 (MH*). 





62 



EP0 661 259 A1 

EXAMPLE 105 
4>[[[(5,6-Dihydro-5.5^imethvl-fl-ph.ny^^^^ 



10 



18 



20 



25 



30 




35 



40 



45 



pound: 'H-NMR (DMSO-d^iTfi 1Z87 (s imT7?/?^T^u iL';^"^ "'S ^5%) of the title conv 

(d. J=4.5 Hz. 2H). 1.24 (s. 6H) MS (TC ) ml -W1 ISii IR^P r^;o« ''"'•^ ^ ^H). 2.27 

Ana,, cared. forC.H.O^, • is hJ. d^^s^H. SlT^^SS^^ir'"' ''''' ^^'^ 
EXAMPLE 106 



5,5-Dtmethvl-5.6^ihii 



hthalene-2-carboxyik: acid. NI.Q-dimathy 



hydroxy amtde (Ulla) 




was then aDowd to stir at room temperature After 2 ll^t n yTT''^ ^« ""^t"^ 

drich. 401 mg. 4.11 mmol) and anh Jdrous pyJJ ni (6» hydroxychloride (Ai- 

room temperature, the reaction mixture was oonZixT^' '"^^ added at 0«C. After 2 houns at 
With brine (2 x 50 mL). dried ovrin ydTus " S^J *^a^t' ^''"'^'^ -"-J 

94%)of the title product; iH-NMR (CD^ 6 7 K^J^T-ToTq h 1?",'?"''^*"'' ^ ^ ^ (Y: 
7.32 (d. J=1.8 Hz, 1H). 6.01 ft j4 5 H^ iwi 1 40 /' ^' "^^^ ^ 7-37 (m, 5H) 

MS (DC,) m/e: 322 (M^O ' ^'^^ (d. J=4.5 Hz. 2H). 1.35 (s. eH); 

EXAMPLE 107 



S.S-Dimethyl-5.6^.hydro-2-formyl.«.ph ^y,nap„,haten>> | i iVof 



80 



55 




63 



EP0 661 259 A1 



20 



30 



40 



MS (DCI) m/e: 263 (MH*). 
EXAMPLE 108 



,J=4.5 HZ.2H). 1.38(s. 6H); 



10 



18 




mL). sodium eyanoborohydride (1 S S.rYmmrwiJ .hlL^S ^ ""^'^ 

lions avery 10 minutes) After le h =>trZZ[ ! •'""'^ P«»od (6 x 29 mg dot- 

of the title product ^H-NI^R (CDQJ: 8 7 83(758 9 h1 2m ^ , o?"^^ *° ^^^^ ''8%) 

(d. J=2.0 Hz. 1H). 6.52 (d. J=8.9 Hz 2H) 5 99 ft ^ J^m f-^T: ^"^^ ^ 1"). ^ M 

3H). 2.35 ft J=4.5 Hz. in). 1^ (,. /^JSo^ o ^8 (mV^ ' ^ ^ 

EXAMPLE 109 

4:K(5.6.Dihyd,o.5,5.dimethy,-^p,eny,^2.naphtha , e n ^ , ,.e th^^^^^^ 




COgH 



45 



60 



EXAMPLE 110 

fm(5.6.D,hydro.5.5^,meH,y,.6^henYiV2.naph«h.iBn,rn.^^^^^^^ „„ 



55 



64 



EP0 661 259 A1 




10 



15 



of the title product 1H-NMR (CDa,;:TMnH^S^Ml2?r^^^^ 
EXAMPLE 111 



^ro-5j5-dimethy 



>-2-naphthalenyqamino]thiocarbonyllbenzoic acid (|i9a) 



25 



30 



35 




EXAMPLE 112 



40 



45 



60 



Methyl 4-mercaptoben2oatB 



To a solution Of 4-mercaptobenzoic acid (Apin 1 72fl 11 I7mm^i\-^ ^ 
was added concentrated sulfuric acid (0 43 ThV«L T ^ " ^"^y^"'"® methyl alcohol (20.0 mL) 

centrated In vacuo, diluted wremJ L^T Mon^^ T T ""^'"'^ ^^''"^^ ^^^'"^ ^6 h, con- 

100 mL). The organic phLetlhen^^ '"^ ^"''^ ""^"^^^^^ bicarbonate (2 x 

vacuo ti give 71^2 S^S^S:^^^^^^ 77^;-;"; - ^"^^"^'^^^ ^" 

Hz. 2H). 3.90 (s. 3H). 3.60 (s. 1H). ^ * ^"^^ ^'^^'^ 2H). 7.29 (d. J=8.7 

EXAMPLE 113 



55 



[(5.6-Dihydro-5-5-dimAfrhy 



IJbenzoic acid, methyl ester (l^^a) 



65 



EP0 661 259 A1 



10 



18 



20 




(190 ma. 0.581 mmd) was at^ed. A tor 2 hT«itJtS^-r T.^*"'"" " "^P'*"'"* LVIIIa 
washed with IN hydiochloric acW fi xM ».( , u """'^ («> mL) »k1 

ch«««tog„phed on^^geC?^^:?^^^^^^^ ~-e„.rated In vacuo a«, .he Jidue 



EXAMPLE 114 



4■[^^(5.6.Dlhyd^^5.5^imethv|.8oh.ny.u .■n.p>halen^^lme>hy.]..„.f.^^,ben^^^ 



25 



30 



35 



40 




Anal, caled. forCjeH^OaSrHzO: C. 76.93; H. 6.11 
Found: C. 76.91; H. 6.03. 

EXAMPLE 115 

1 ^-Dlhydn>.1,1.dlmethy|.6.nltro^/trif...»,» ^ ethanesu[fonvl«vy| n.rh>h,,.„., ^. 



45 



80 



55 




-78=?v:as1SS^r5;j^^^^^^^^^ ""-'^ tetrahydrofuran (10 .L, at 

N-(2-pyridy.)trifnmide (12.05^^4 32^^78^^^^^^^ '^"^ and then 

water and extracted with ethyl ace^e (2 x i S.f T^e^^^^^^ 

vacuo. The residue was chr<Ltog«Dhed on sS IS .f^!. -.u "•"centrBted in 

9 (Y: 70%) of the title produ^SS (CoS y TAtlt S^ "iZ^^ ""^"^'^ ''^^^"^J 



66 



EP0 661 259 A1 

EXAMPLE 116 

1,2>Dihydro-1.l.dimethvl>6.nltrn.^p henylnaDhthal«n^ p vn.^ 



10 



18 



20 



28 




and tributylphenyltin (6.17 fl.%.78ZoTirXl?^^^^^ 

C the mWure was dWuted w«h water aZeSraSLKhJ^^ <5.0 ml). After 16 h. at 60- 

combined, stirred over a saturated a^Z^^^'^^^'^ ^^jc 100 ml). The organic phases were 
trated in vacuo. The residue was chro^tS^hl^L^lf^'r, ""^ "^^^'^-^ "'"ce"- 
glve 1.93 g (Y: 90%) of the title pSJS SX^COa s fii M^f' . ^•^'^'^ «» 

1H). 7.50 (d. J=8.5 Hz. 1 H). 7.36;m. 6 I^jS sS^H) 2 il i l!;';^' ^ •'^^-S Hz. 

m/e:280(MH^. ' * ' •* W J«4.5 Hz. 2H), 1.39 (s. 6H); H^S (DCI) 

EXAMPLE 117 

5 ,S-Dlmethy|.8.phenyl-S.6-dihy dr,vn«nh. ^alene.2.vlamin» | i v....^ 



30 



5D 




period of 1.5 h in four equal aliquots The re^Tt nTm^w' ^ ^ ^^-5° 9> ^<'<'«d over a 

temperature, the reactten mx Jre ^^^nlZ^^^ZZTJl^T'"' ? 
over anhydrous magnesium sulfate and concentri in vfl^ ^,''"'a^"'«=Phase was separated, dried 
NMR (COaj: S 7.35 (m. 5H). 7.15 (d. S^^Tw^e ^^ J-« If /u^^ ''''' 

s.s(..^.5^i^.3.5(..2^.^a.3i...^.;si5:js;r^^^^^^^^^^ 



« EXAMPLE 118 

4>nr(5.6-DihvdrQ-5-fUH.n^.K^._a r-ienyl)-2-naDhth.l.nw 



benzofc add, methyl ester ( 




67 



EP0 661 259 A1 



thyQamino]benzotc acid, methyl ester (P^a). 1.35 g (5.38 mmol) of compound LXIIIa and methyl 4-formylben- 
zoate (Aldrlch. 723 mg, 4.41 mmol) gave 1.38 g (Y: 79%) of the title product; ^H-NMR (CDCI3): 6 7.95 (d, Js8.5 
Hz, 2H). 7.29 (m, 7H). 7.16 (d. J=8.3 Hz. 1H). 6.47 (dd. J=8.3, 2.6 Hz, 1H). 6.29 (d, J=2.6 Hz, 1H). 5.94 (t, 
J=4.5. 1H). 4.53 (s, 2H), 3.91 (s. 3H), 2.30 (d. J=4.5 Hz, 2H), 1.29 (s. 6H): MS (DCI) m/e: 398 (MH^. 

EXAMPLE 119 

4-[g(5,6-Dihydrc>-5,5-dimethyl-Bi^henyl)-2--naphthalenyl]aminolmethynbenzoic acid (1^) 



To a solution of compound |2»a (1 .38 g. 3.48 mmol) In a 1 :1 mixutre of ethyl alcohol/tetrahydrof uran (1 5.0 
mL) was added 10 N NaOH (35.0 mmol, 3.5 mL) at room temperature. After 16 h an excess of IN HCI (100 
mL) was added and the precipitate collected t>y vacuum filtration to give 1.28 g (Y: 96%) of the title product 
as a hydrochloride salt; ^H-NMR (DMSO-dg): 6 7.84 (d. J=8.2 Hz. 2H). 7.36 (d. J=8.2 Hz, 1H). 7.31 (m, 5H), 
7.15 (m, 4H). 6.99 (bs, 1H), 6.36 (bs, 1H). 5.90 (t. J=4.5 Hz, 1H), 4.32 (s, 2H), 2.21 (d. J=.5 Hz, 2H), 1.19 (s, 
6H); MS (DCI) m/e: 384 (MH*); IR (KBr): 3420, 2958, 1694, 1606 cm-^. 

Anal, calcd. for CjeHzsNiOz-LO HCI: C, 72.80; H. 6.34; N. 3.27. Found: C, 72.98; H, 6.09; N. 3.14. 
EXAMPLE 120 

3,3-Dimethyl-6-nitro-indan-1-one 



To a solution of 3,3-dimethylindan-1-one (LXIV) (16.3 g. 50.9 mmol) (Harms, W. M. and Eisenbraum. E. 
J. Org. Prep. Proc. int 1972, 4. 67-72) in 56 mL of sulfuric acid was slowly added 4.18 mL of 70% nitric acid 
in 20 mL of sulfuric acid at 0-5 °C. After being stirred for 1 hour, the reaction mixture was poured Into 600 g of 
ice. The precipitates was filtered and washed with water. The solids collected were dissolved in 600 mL of ethyl 
acetate and washed with NaHCOs (80 mL X 2), dried over nnagnesium sulfate, and evaporated. The residue 
was triturated with methanol to give 22.2 g of the title compound as yellow solids; ^H-NMR (CDCI3) 6 1.49 (s, 
6 H). 2.71 (s, 2 H), 7.68 (d, J = 8.4 Hz, 1 H), 8.48 (dd. J « 2.0, 8.4 Hz, 1 H). 8.53 (d. J = 2.0 Hz, 1 H); MS m/e 
206 (MH^. 

Anal, calcd. for CiH^NOa: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.33; H. 5.33; N, 6.86. 
EXAMPLE 121 

6-Amino-3,3-dimethyl'indan'1-one (LXV) 




O 




68 



EP0 661 259 A1 




3,3-Dlmethyl-6-nltro-lndarv1-one (22.2 g, 54.1 mmol) and pratlnum oxide (0.44 g. 1.94 mmol) In 30 mLof 
ethyl acetate and 60 mL of methanol was hydrogenated on a Pan- Shaker for 40 min. The mixture was filtered 
through a pad of celite. The filtrate was evaporated and the residue was triturated with hexane to give 18.4 g 
(97% yield) of the title product as yellow solids; ^H-NMR (CDOa) 5 1 .38 (s, 6 H), 2.56 (s. 2 H). 6.98 (d. J = Z3 
Hz. 1 H). 7.02 (dd. J = 2.3. 8.2 Hz. 1 H). 7.30 (d, J = 8.2 Hz. 1 H); MS m/e 176 (MH*). 
Anal, calcd. for C„H„N03: C. 75.40; H, 7.48; N. 7.99. Found: C, 75.07; H, 7.45; N, 7.94. 

EXAMPLE 122 

6-Hydroxy-3.3«dlmethyl-indan-1>one (LXVI) 

A solution of sodium nitrite (14.8 g. 214 mmol) in 30 mL of water was slowly added to the solution of 6- 
amino-3,3-dlmethyl-lndan-1-one (14.0 g. 85.8 mmol) In 30 mL of 48% telrafluoroborlc acid and 30 mLof water 
at 0-5 X. After being stirred for 30 min. the mUture was filtered, and the solids were washed with cold 6% 
tetrafluoroboric acid and dried in vacuum. The solids were then added in several portions into a tailing solution 
of 50 mL of sulfuric acid In 0.5 liter of water. After ref luxing for 1 hour, the solution was cooled to room tem- 
perature and extracted with ethyl acetate (100 mLX 3). The combined extracts were dried over magnesium 
sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane = 1:10 to 1:2) to 
give 7.60 g (50% yield) of the title compound as a solid; ^H-NMR (CDCI3) 6 1.40 (s, 6 H). 2.64 (s. 2 H) 713 
(s. 1 H).7.18 (d. J = 8.2 Hz, 1 H). 7.39 (d. J = 8.2 Hz, 1 H); MS m/e 177 (MH*). 
Anal, calcd. for C11H12O2: C, 74.98; H, 6.86. 
Found: C. 74.81; H. 6.76. 

EXAMPLE 123 

TrifluoromethanesuHbnic add 1,1-dlmethyl-3-oxo-lndan-5-yl ester 




To a solution of 6-hydrQxy-3.3-dimethyl-indan-1-one (4.01 g. 24.4 mmol) and 4-dJmethylaminopyridine 
(DMAP, 5.97 g, 48.9 mmol) in 30 mL of methylene chloride was slowly added triflic acid anhydride (9.65 g, 
34.2 mmol) at -78 'C. After stirring at room temperature for 1 hour, the mbdure was diluted with methylene 
chloride (60 mL), washed with 1 N HQ (1 0 mLX 2) and water (1 0 mL). dried over magnesium sulfate, and evapo- 
rated. The residue was purified by flash chromatography (EtOAc:hexane = 1:10 to 1:5) to give 5.58 g (74% 
yield) of the title compound; ^H-NMR (CDCI3) 5 1 .46 (s. 6 H). 2.67 (s. 2 H). 7.51 (dd. J = 2.3, 8.4 Hz. 1 H) 7 57 
(d. J = 2.3 Hz. 1 H). 7.60 (d, J= 8.4 Hz. 1 H): MS m/e 309 (MH*). 
Anal, calcd. for Ci2H„F304S: C,46.75; H.3.60. 
Found: C,46.83; H. 3.58. 

EXAMPLE 124 

Methyl 1.1-dlmethyl-3-oxo-indan'5-carboxylate (LXVII) 

A solution of trifluoromethanesulfonic acid 1 ,1-dimethyl-3-oxo-lndan-5-yl ester (3.08 g. 10.0 mmol). trie- 
thylamine (2.02 g. 20.0 mmol). palladium acetate (0.11 g, 0.50 mmol) and 1, 3- bis(dlphenylphosphino) propane 
(dppp, 0.21 g, 0.50 mmd) in 30 mL of anhydrous dimethylsulfoxide and 20 mLof methanol was saturated with 



69 



EP0 661 259 A1 



carbon monoxide for 10 min, and then stirred under a balloon filled with carbon monoxide at 65-70 for 2 
hours. Methanol was evaporated, and the resulting solution was diluted with 50 mL of water, extracted with 
ethyl ether (40 mL X 4). The combined extracts were dried over magnesium sulfate and evaporated. The re- 
sidue was purified by flash chromatography (EtOAc:hexane = 1:20 to 1:5) to give 1.98 g (91 % yield) of the 
5 title compound as light yeHow solids; iH-NMR (CDO^) S 1.45 (s. 6 H). 2.65 (s, 2 H), 3.94 (s, 3 H). 7.58 (dd, J 
= 8.1 Hz, 1 H), 8.30 (dd, J = 1.6. 8.1 Hz. 1 H), 8.36 (d, J = 1.6 Hz, 1 H); MS m/e 219 (MH^. 
Anal, calod. for CtaH^Os: 0,71.54; H, 6.47. 
Found: 0,71.71; H,6.46. 

10 EXAMPLE 125 

Methyl 1,1-dinf>ethyl-3-(trifluoromethanesulfonyloxy>-1H-indene-5-carboxylate 



20 




To a solution of methyl 1.1-dimethyl-3-oxo-lndan-5-carboxylate (0.90 g, 4.12 mmol) and 2,6-di-tert-butyl- 
25 4-melhyIpyridine (1.10 mg, 5.36 mmol) in 10 mL of methylene chloride was added triflic acid anhydride (1.39 
g, 4.94 mmol) at -78 *»C. After being stirred at room temperature for 16 hours, the mixture was diluted with 70 
mL of ethyl ether, washed with 1 N HCI (20 mL), dried over magnesium sulfate, and evaporated. The residue 
was purified by flash chromatography (EtOAcrhexan e = 1 : 20 to 1 :5) to give 1 .23 g (85% yield) of the title com- 
pound; iH NMR (CDCI3) 6 1.41 (s. 6 H).3.95 (s, 3 H). 6.30 (s, 1 H), 7.44 (d. J = 7.8 Hz, 1 H). 7.99 (s. 1 H). 8.06 
30 (d, J = 7.8 Hz. 1 H); MS m/e 351 (MH^. 

EXAMPLE 126 

Methyl 1.1-dimethyl-3-phenyl-1H-lndene-5>carboxylate (LXVIIIa) 



Ph 



40 




Methyl 1,1-<llmethyl-3-(trifluoromethanesulfonyloxy)-1H-lndene-5-carboxylate (580 mg, 1.86 mmol), 
45 lris(dlbenzylideneacetone)dipalladium (0) (Pdzdbaa. 17 mg. 0.02 mmol), triphenylarsine (46 mg, 0,15 mmol). 
lithium chloride (240 mg, 5.59 mmol) and phenyltributyltin (680 mg. 1.86 mmol) in 5 mL of 2-melhyl pyrrolidi- 
none were stirred at 55 ''C for 1.5 days. The mixture was diluted with water (30 mL), and extracted with ethyl 
ether (30 mL X 3). The combined extracts were dried over magnesium sulfate and evaporated. The residue 
was purified by flash chromatography (EtOAc:hexane = 1: 20 to 1: 5) to give 0.43 g (83 % yield) of the title 
50 compound as a white solid; 'H-NMR (CDCI3) 6 1.41 (s, 6 H), 3.91 (s, 3 H), 6.48 (s, 1 H), 7.39-7.62 (m, 6 H). 
7.99 (d. J = 6.8 Hz. 1 H), 8.14 (s. 1 H); MS m/e 279 (MH^. 
Anal, calod. for 0,»H,e02. 0.25 H2O: C, 80.68; H. 6.49. 
Found: C, 80.76; H,6.41. 

55 EXAMPLE 127 

Methyl 4-[(1 .1 -Dimethyl-3-phenyl-1 H-tndene-5-carfaonyl)amino]benzoate 



70 



EP0 661 259 A1 



5 




10 Methyl 1.1-dimethyl-3-phenyl-1H-lndene-5-carboxy!ate (315 mg, 1.13 mmol) was stirred with 10 N NaOH 

(1.1 mU 11.0 mmol) in 5 mL of methanol and 10 mL of tetrahydrof uran at 60 'C for 1.5 hours. The solution 
was concentrated under reduced pressure and acidified with 1 N HO (15 mL), extracted with ethyl acetate 
(1 5 mL X 3). The combined extract s were washed with water (1 0 mL), dried over magnesium sulfate, and evapo> 
rated. The residue was dried In vacuum and dissolved in 2.5 mL of methylene chloride. To the solution was 

IS added oxalyl chloride (348 mg, Z74 mmol) and 2 drops of dimethylformamide at 0 ""C. The solution was stirred 
at 0 'C for 30 min and at room temperature for 30 mln. The mixture was evaporated and dried In vacuum. The 
residue was stirred with methyl 4-amlnoben2oate (181 mg, 1.32 mmol) in 2 mL of anhydrous pyridine for 18 
hours. Excess pyridine was evaporated and the residue was diluted with 20 mLof 2 N HCI. extracted with ethyl 
ether (30 mL X 4). The combined extracts were washed with water (10 mL), dried over magnesium sulfate and 

20 evaporated. The residue was purified by flash chromatography (EtOAc: hexane = 1: 20 to 1: 5) to give 372 mg 
(85% yield) of the title compound as a glassy mass; ^H-NMR [COa^ d 1.43 (s. 6 H), 3.91 (s, 3 H), 6.52 (s, 1 
H), 7.40-7.50 (m, 4 H). 7.59-7.61 (m. 2 H). 7.72-7.75 (m. 3 H), 7.96 (s, 1 H), 8.00 (bs. 1 H). 8.05 (d. J = 8.7 Hz, 
2 H); MS m/e 398 (MfT). 

Anal, calcd. for C^HzzNOz. 0.125 H2O: C.78.12; H, 5.93; N, 3.50. 
25 Found: C, 77.97; H, 5.50; N. 3.24 

EXAMPLE 128 

4-[(1,1-Dimethvl-3-phenyl-1H>indene-5-carbonyl)amino]benzoic acid (l^a) 

30 



35 




40 Methyl 4-[(1 ,1-dimethyl-3-phenyl-1 H-indene-5-carbonyl)aminoIbenzoate (359 mg, 0.90 mnrral) was stin-ed 

with 4.5 mL of 2 N NaOH in 5 mL of methanol and 5 mL of tetrahydrof uran for 1 0 hours. The solution was acidi- 
fied with IN HCI and concentrated under reduced pressure. After addition of 15 mLof water, the mixture was 
extracted with ethyl acetate (15 mL X 3). The combined extracts were washed with water (10 mL), dried over 
magnesium sulfate, and evaporated. The residue was triturated in ether-hexane to give 326 mg (94 % yield) 

45 of the title compound as solids; ^H-NMR (DMSO-dg) 5 1.39 (s, 6 H). 6.68 (3. 1 H), 7.39-7.53 (m. 3 H), 7.64- 
7.68 (m, 3 H), 7.85-7.97 (m, 6 H), 10.54 (s, 1 H). 12.75 (bs. 1 H); MS m/e 384 (MH"). 
Anal, calcd. for C2SH21NO3. 0.25 H2O: C 77.39; H. 5.46; N, 3.61. 
Found: C. 77.26; H. 5.51; N, 3.52 

50 EXAMPLE 129 

1,1«Dlmethyl*5-nltro>3-(trifluoromethanesulfDnyloxy)-1H-indene 



55 



71 



EP0 661 259 A1 



O 




'2 



To a solution of 3,a.dimelhyl-6-nitro-lndan-1-one (LXIX) (1.00 g, 4.65 mmol) and 2,6-di-tert-butyl-4-me- 
thylpyridine (1.19 5.80 mmol) in 10 mL of methylene chloride was added trifiic acid anhydride (1.57 g, 5.58 
mmol) at -78 »C. After being stirred at room temperature for 16 hours, the mixture was diluted with 1 N HCI 
(20 mL) and extracted with ethyl ether (30 mL X 3). The combined extracts were washed with water (20 mL). 
dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography (EtOAc: 
hexane = 1: 20 to 1:10) to give 1.37 g (87% yield) of the title compound as an oil; ^H-NMR (CDOa) 6 1.45 (s, 
6 H). 6.43 (s. 1 H). 7.53 (d, J = 8.3 Hz, 1 H), 8.15 (d, J = 2.0 Hz 1 H). 8.24 (dd. J = 2.0. 8.3 Hz. 1 H); MS m/e 
338 (MH^. 

Anal, calcd. for C^zH^oFsNOgS: C. 42.73; H, 2.99; N. 4.15. 
Found: C, 42.70; H. 2.80; 4.1 0. 

EXAMPLE 130 

1 ,1-Dlmethyl-5-nitro-3-phenyl-1 H-indene (LXXa) 



1,1-Dlmethyl-5-nitro-3-(trifluoromethanesulfonyloxy)-1H-indene (1.32 g. 2.89 mmol), tris(dibenzyli- 
deneacetone)dipalladium (0) (21 mg, 0.02 mmol). triphenylarsine (70 mg. 0.23 mnrwl), lithium chloride (0.37 
g. 8.67 mmol) and phenyltributyltin (1.06 g. 2.89 mmol) were stinred at 60 ''C for 48 hours. The mixture was 
diluted with water (30 mL), extracted with ethyl ether (30 mL X 3). The combined extracts were dried over mag- 
nesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc: hexane = 1: 25 to 
1 : 5) to give a solid which recrystalllzed from hexane to give 575 mg (75 % yield) of the title compound as light 
yellow crystals; iR-NMR (CDCIJ 6 1.44 (s, 6 H), 6. 58 (s, 1 H), 7.40-7.60 (m, 6 H), 8.18 (d, J = 2.0, 8.2 Hz, 1 
H). 8.32 (d. J = 2.0 Hz. 1 H); MS m/e 266 (MH^. 
Anal, calcd. for C,7H,5N O2: C, 76.96; H. 5.70; N. 5.28. 
Found: C. 76.71; H. 5.69; N, 5.2Z 

EXAMPLE 131 

5-Amino-1 ,1-dimethyl-3-phenyl-1 H-indene (LXXia) 



To a mixture of 1,1-dimethyl-5-nitro-3-phenyl-1H-indene (0.56 g, 2.11 mmol) in 5 mLof benzene was added 
33% ferric chloride (1 mL) and 4 mLof water. The mixture was stiffed at reflux and iron powder (1.00 g, 5.28 



Ph 




Ph 




72 



EP0 661 259 A1 



mmol) was added In four portions during 2 hours. The resulting mixture was stirred at reflux for additional 18 
hours. The mixture was diluted with 20 mL of water and 20 mL of ethyl acetate, and filtered through a pad of 
cellte. The filtrate was extracted with ethyl acetate (20 mLX 3). The combined extracts were dried over mag- 
nesium sulfate to give 0.49 g (98% yield) of the crude title compound which was not further purified and used 
5 in the next reaction; ^H-NMR (CDCI3) 5 1 .37 (s. 6 H), 6.40 (s. 1 H), 8.71 (dd. J = 2.0, 7.9 Hz. 1 H). 8.93 (d, J = 
2.0 Hz. 1 H), 7.19 (d. J = 7.9 Hz. 1 H). 7.36-7.58 (m, 5 H); MS m/e 236 (MH*). 

EXAMPLE 132 

Methyl 4-(1.1-dimethyl-3-phenyi-1 H-tnden-5-yl)aminolcartK)nynbenzoatB 



IS 



20 



25 



30 




COsMe 



5-Amino-1.1-dlmelhyl-3.phenyHH-indene (0.49 g, 2.06 mmol) and terephthalic monomethyl ester chlor- 
ide (0.49 g, 2.47 mmol) were stirred In 5 mLof pyridine for 1 8 hours. The solvent was evaporated and the residue 
was diluted with 1 N Ha (20 ml), extracted with ethyl acetate (20 mLX 3). The combined extracts were washed 
with saturated NaCI solution, dried over magnesium sulfate, and evaporated. The crude product was purified 
by flash chromatography (EtOAcihexane =1 :1 0 to 1 :5) to give 772 mg (94% yield) of the title compound which 
crystallized from EtOAc-hexane to give 720 mg of crystals; ^H-NMR (CDaj 6 1 .41 (s, 6 H). 3.96 (s, 3 H) 6 47 
(s. 1 H), 7.37-7.60 (m, 7 H). 7.68 (s. 1 H). 7.84 (s. 1 H). 7.94 (d, J = 8.3 Hz, 2 H). 8.16 (d. J = 8.3 Hz. 2 H); MS 
m/e 398 (MH*). ' 
Anal, calcd. for CasHzaNQa : C, 78.57; H, 5.83; N, 3.52. 
Found: C, 78.45; H. 5.76; N, 3.41. 



EXAMPLE 133 



4-11(1 , 1-Dimethyl-3-phenvl-1 H-inden-5-yl)amtno]carfaonyl]benzolc acid (P^a) 




CO2H 



45 



50 



Methyl 4-[[(1,1-dimethyl-3-phenyl-1H-inden-5-yl)amino]carbonylJben2oate (325 mg, 0.82 mmol), 4.1 mL 
of 2 N NaOH in 1 0 mL of tetrahydrof uran and 1 0 mL of methanol were stirred for 2 hours. The mixture was 
concentrated and acidified with 1 N HCI (20 mL). extracted with ethyl acetate (35 mLX 2). The combined ex- 
tracts were washed with water (10 mL). dried over magnesium sulfate, and evaporated. The residue was tri- 
turated In ether-hexane to give 246 mg (78 % yield) of the title compound as white solids; ^H-NMR (DMSO- 
de) 5 1.35 (s. 6 H). 6.58 (s, 1 H). 7.38-7.70 (m, 7 H). 7.73 (d. J = 7.9 Hz. 1 H). 7.90 (s. 1H), 8.04 (s, 4 H). 10.38 
(bs, 1 H). 13.25 (bs, 1 H); MS m/e 384 (MH^. 
Anal, calcd. for CasHj^NOa . 0.25 H2O: C. 77.40; H. 5.59; N. 3.61. 
Found: C. 77.24; H, 5.33; N. 3.41. 



55 EXAMPLE 134 



Methyl 4-(1,1-dimethyl-3-oxo-indan-5-yloxymethyl)benzoate (LXXIIa) 



73 



EP0 661 259 A1 



5 




10 6-Hydroxy-3.3-dimelhyl-indan-1-one (0.72 g, 4.37 mmol) in 5 mLof dimelhylformainide was added sodium 
hydride (0.16 g. 6.55 mmol) atO ''C. After stirring for 30 min, methyl 4-bronr»methylben2oate (1 .00 g, 4.37 mmol) 
was added. The resulting mixture was stirred at 0" C for 1 hour and at room temperature for 2 houre. The mixture 
was cooled to 0 and acidified with 1 N HQ. The solvent was evaporated and the residue was acidified with 
20 mLof 1 N HO and extracted with ethyl ether (30 mL X 3). The combined extracts were dried over magnesium 

15 sulfete and evaporated. The residue was purified by flash chromatography (EtOAc: hexane = 1 ; 20 to 1 : 4) to 
give 0.68 g (48% yield) of the title compounds as a solid: ^H-NMR (CDCy 6 1.41 (s, 6 H), 2.61 (s, 2 H), 3.93 
(s. 1 H), 5.15 (s. 2 H). 7.18 (d. J = 2.5 Hz. 1 H), 7.30 (d, J = 2.5, 8.4 Hz, 1 H), 7.42 (d. J = 8.4 Hz. 1 H), 7.51 
(d, J = 8.3 Hz. 2 H). 8.07 (d. J = 8.3 Hz. 2 H); MS m/e 325 (MH^. 
Anal, calcd. for C20H20O4 : C, 74.06; H, 6.21. 

20 Found: C. 73.99: H. 6.24. 

EXAMPLE 135 

Methyl 4-f1,1-dimethyt-3-(trifluoromethanesulfonyloxy)-1H-tndene»5-yloxymethyl]benzoate 

25 



o 



30 




To a solution of methyl 4.(1 .1-dimethyl-3-oxo-lndan-5-yloxymethyl)benzoate (675 mg, 2.08 mmol) and 2.6- 
dl-tert-buty|.4-methylpyrldine (534 mg, 2.60 mmol) in 5 mL of methylene chloride was added triflic acid an- 
hydride (705 mg. 2.50 mmol) at -78 *»C. After being stirred at room temperature for 16 hours, the mfarture was 
diluted with 1 N HCI (20 mL). extracted with ethyl ether (20 mLX 3). The combined extracts were dried over 

40 magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc: hexane = 1: 
20 to 1:10) to give 849 n\g (95% yield) of the title compound as a solid; ^H-NMR (CDO^ 6 1.37 (s, 6 H). 3.93 
(s. 1 H), 5.15 (s. 2 H). 6.24 (s. 1 H). 6. 90-6.94 (m. 2 H). 7.25 (d over CHCIa. J = 8.8 Hz. 1 H), 7.53 (d, J = 8.7 
Hz, 2 H), 8.08 (d. J = 8.7 Hz. 2 H); MS m/e 457 (MH"). 
Anal, calod. for C^iHtoFaOfiS: C, 55.26; H, 4.20. 

45 Found: C. 55.39; H. 4.08. 

EXAMPLE 136 

Methyl 4-(1.1-dimethyl-3>phenyl-1 HHnden-&-yloxymethyl)benzoate 



55 




7- 



EP0 661 259 A1 



Methyl 4-I1,1-dimethyl-3-(trifluoromethanesulfonyloxy)-1H-lndene-5-yloxymethyl]benzoate (838 mg, 
1.84 mmol), tris(dibenzylld6neacetone) dipalladlum (0) (17 mg, 0.02 vnmcA), triphenylarsine (64 mg, 0.20 
mmol). lithium chloride (234 mg, 5.51 mmol) and phenyltributyltin (676 mg, 1.84 mmol) were stirr d at 60 ""C 
for 18 hours. The mixture was diluted with water (30 mL), extracted with ethyl ether (30 mL X 3). The combined 
extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatogra- 
phy (EtOAc: hexane = 1: 25 to 1: 10) to give a product which recrystallized from EtOAc-hexane (1:20 to 1:t0) 
to give 454 mg (64 % yield) of the title compound as crystals; ^H-NMR (CDCI3) 6 1.38 (s. 6 H), 3.93 (s. 1 H). 
5.13 (s, 2 H), 6. 44 (s, 1 H). 6.86 (dd. J = 2.2. 8.1 Hz. 1 H). 7.11 (d. J = 2.2 Hz, 1 H), 7.27-7.55 (m, 8 H), 8.06 
(d, J = 8.1 Hz, 2 H): MS m/e 385 (MH*). 
Anal, calcd. for C2eH2403. 0.125 H2O: C, 80.75; H. 6.32. 
Found: C. 80.76; H, 6.19. 

EXAMPLE 137 

4-[(1,1-Dimethyl-3-phenyl-1H-inden-5-yloxymethyl)benzolc acid (l^a) 



Methyl 4-(1,1-dimethyl-3-phenyl-1H-inden-5-yloxymethyl)benzoate (300 mg. 0.78 mmol) and 3.9 mL of 2 
N NaOH In 5 mL of tetrahydrof uran and 5 mL of methanol were stirred at room temperature for 1 6 hours. TTie 
mbdure was concentrated and acidified with 1 N HCI (10 mL), extracted with ethyl acetate (20 mL X 3). The 
combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The re- 
sidue was crystallized from ether-hexane to give 247 mg (85% yield) of the title compound as white crystals; 
iH-NMR(DMSO-de) S 1.31 (s. 6 H), 5.20 (s, 2 H). 6. 57 (s, 1 H). 6.89 (dd, J = 1.1, 8.2 Hz. 1 H), 7.02 (d. J = 1.1 
Hz, 1 H). 7.36-7.57 (m. 8 H). 7,95 (d. J = 8.3 Hz. 2 H). 12.94 (bs. 1 H); MS m/e 371 (MH*). 
Anal, calcd. for C25H22O3. 0.25 H2O: C, 80.08; H, 6.05. 
Found: C, 80.17; H, 5.86. 

EXAMPLE 138 

6-Bromo-3,3-dlmethyl-indan-1-one (LXXIV) 



To aluminum chloride (4.16 g, 31.2 mmol) in a flask was added 3,3-dlmethyH-indan-1-one (2.00 g, 1^5 
mmol) at 90-100 •C. After stining for 15 min, bromine (2.39 g. 15.0 mmol) was slowly added. The mbdure was 
starred at 100 **€ for 1 hour and then quenched with Ice-water (200 g). extracted wllh ethyl acetate (40 mL X 
3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by 
flash chromatography (EtOAc: hexane = 1 : 20 to 1 :1 5) to give a crude product which recrystallized from MeOH- 
EtOAc to give 1.23 g (41 % yield) of the title compound as colorless crystals; ^H-NMR (CDQ,) 5 1.42 (s, 6 H), 
2.61 (s. 2 H), 7.39 (d, J = 8.2 Hz. 1 H). 7.72 (dd, J = 2.0, 8.2 Hz. 1H), 7.82 (d, J = 2.0 Hz, 1 H); MS m/e 239 
(MH^). 

Anal, calcd. for CnH^iBrOs: C. 55.26; H. 4.64. 
Found: C, 55.19; H. 4.61. 




O 




75 



EP0 661 259 A1 

EXAMPLE 139 

Methyl 4-[2-(1,1-dimethyl-3-oxo-indan-5-yl)vlnyl]befizoate (LXXVfei) 




6-Bromo-3.3-dimethy1-indan-1-one (1.20 g, 5.02 mmol). methyl 4-vinylbenzoate (1.63 g, 10.0 mmol), pal- 
ladium acetate (56 mg, 0.25 mmol), tetrabutylammonlum chloride hydrate (1.53 g, 5.52 mmol), and sodium bi- 
carbonate (1.05 g. 12.6 mmol) were stirred In 10 mL of anhydrous N.N-dlmethylformamlde at 80-100 X for 8 
hours. The mbcture was diluted with water (100 mL). extracted with methylene chloride (50 mLX 3). The com- 
bined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chro- 
matography (CHjCts: hexane *= 1: 1 to 1:0, then CHjClarEtOAc = 10:1) to give 1.12 g (70 % yield) of the title 
compound as a yellow solid; ^H-NMR (CDCIj) 5 1.45 (s. 6 H), 2.64 (s. 2 H), 5.30 (s. 3 H). 7.18 (d. J = 16.5 Hz. 
1 H). 7.26 (d. J = 16.5 Hz. 1 H). 7.52 (d, J = 8.1 Hz. 1 H). 7.58 (d. J = 8.5 Hz. 2 H). 7.78 (d. J = 1.7. 8.1 Hz, 1 
H). 7.86 (d. J = 1.7 Hz. 1 H). 8.05 (d. J = 8.5 Hz. 2 H); MS m/e 321 (MH^. 
Anal, calcd. for CjiHaoOa: C. 78.18: H. 6.3Z 
Found: C, 78J22; H. 6.26. 

EXAMPLE 140 

Methyl [2-[1,1-dlmethyl-3»(trifluoromethanesuifonyloxy)-1H-indene-5-yllvinyllbenzoate 



O 




To a solution of methyl 4.[2-(1,1-dimethyl-3-oxo-indan-5-y!)vinyl]ben2oate (450 mg, 1.40 mmol) and 2.6- 
dl-tert.butyl-4-methylpyridlne (345 mg, 1.68 mmol) In 5 mL of methylene chloride was added triflic acid an- 
hydride (434 mg. 1 .54 mmol) at -78 'C. After stirring at room temperature for 1 6 hours, the mixture was diluted 
with 1 N Ha (20 mL), extracted with ethyl ether (20 mL X 3). The combined extracts were dried overmagnesium 
sulfate and evaporated. The residue was purified by flash chromatography (CH2CI2; hexane = 1: 2 to 1:1) to 
give 606 mg (95% yield) of the title compound as a solid; ^H-NMR (CDCI3) 5 1.41 (s. 6 H). 3.94 (s. 3 H), 6.27 
(s. 1 H). 7.15 (d. J = 16.3 Hz, 1 H). 7.27 (d. J = 16.3 Hz. 1 H). 7.37 (d. J = 8.2 Hz. 1 H), 7.49 and 7.50 (d over 
8, J = 8.2 Hz, 2 H). 7.59 (d, J = 8.4 Hz , 2 H), 8.05 (d. J = 8.4 Hz . 2 H); (MS m/e 453 (MH^. 
Anal, calcd. for C22H10F3O6S: C. 58.40; H, 4.23. 
Found: C. 58.38; H. 4.00. 

EXAMPLE 141 

Methyl 4-[2-(1.1-dimethyl-3-phenyl-1 H-inden-5-yl)vinyllbenzoate 



76 



EP0 661 259 A1 




Methyl [2-[1 J-dimemyl-3-(trifluoromelhanesulfonyloxy)-1H-indene-5-yI]vlnyl]benzoate (590 mg, 1.30 
mmol), tris(dibenzylldeneac8tone)d(palladlunfi (0) (48 mg, 0.05 mmol). triphenylarsine (64 mg, 0.20 mmol), li- 
thium chloride (1 66 mg. 3.9 1 mmol) and phenyltributylt in (525 mg. 1 .43 mmol) were stirred at 95 for 1 6 hours. 
The mixture was diluted with water (75 mL), extracted with ethyl acetate (20 mL X 2) and ethyl ether (20 mL 
X 2), The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by 
flash chromatography (EtOAc: hexane = 1: 25 to 1: 10) to give a product which recrystalllzed from EtOAc- 
hexane to give 311 mg (63 % yield) of the title compound as yellow solids; <H NMR (CDCI3) a 1.42 (s. 6 H). 
3.93 (s, 3 H). 6.45 (s, 1 H). 7.11 (d. J = 18.3 Hz. 1 H). 7.29 (d, J = 16.3 Hz. 1 H), 7.41-7.65 (m. 10 H). 8.02 (d, 
J = 8.4 Hz, 2 H). 

EXAMPLE 142 

4-t2-(1,1-dimethyl-3>phenyl-1H-mden-5>yl)vinyllbenzoic acid (l^^a) 




Methyl 4-t2-(1,1-dimethyl-3-phenyf-1H-inden-5-yl)vinyl]benzoate (294 mg. 0.77 mmol) and 0.77 mLof 10 
N NaOH in 7 mL of tetrahydrofuran and 5 mL of methanol were stirred at reflux for 1 hour. The mbcture was 
concentrated and acidified with 1 N HO (10 mL), extracted with ethyl acetate (30 mL X 2). The combined ex- 
tracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was tri- 
turated in hot methanol to give 276 mg (90 % yield) of the title compound which contained a moiecuie of me- 
thanol; 1H-NMR (DMSO-dfl) 5 1.34 (s. 6 H), 3.14 (s. 3 H), 6.58 (s. 1 H), 7.25 (d, J = 16.4 Hz. 1 H), 7.37-7.71 
(m. 11H). 7.90 (d, J = 8.3 Hz. 2 H); MS m/e 367 (MH^. 
Anal, calcd. for CasHzeOg. CH3OH: C. 81.38; H. 6.58. 
Found: C. 81.18; H. 6.78. 

EXAMPLE 143 

N-(2s)vrldyl)triflimide 



The title compound was prepared by procedure of Comins & Dehghani, Tetrahedron Lett,, Vol. 33 No 42 
1992, p. 6299. iH NMR (CDCI3): 6 8.66 (m. 1H). 7.95 (m. 1H), 7.56 (m. 1H), 7.48 (d. 1H). MS (DCI) m/e: 359 




77 



EP0 661 259 A1 

Example 144 

* ^•in(5»6-Pih ydro-5,5^tmethyl-8-phenyl)-2>naphthalenyq(arfeonyl1amino^2-^ acid, phenyl es~ 



10 



15 




Using the method given for the preparation of the 8-(2-fIuorDphenyf) derivative l^g. 230 mg (0.83 mmol) 
20 of compound XVIIIa and phenyl 4-amlnosalicylate {Aldrich; 190 mg, 0.83 mmol) gave 193 mg (Y: 48%) of the 
title product; ^H-NMR (COO^): 5 8.03 (d. J=9.3 Hz, 1H), 7.75-7.71 (m, 2H), 7.51-7.19 (m. 13H). 6.09 (t, J=4.5 
Hz, 1H). Z40 (d, J=4.5 Hz, 2H), 1.38 (s, 6H); MS (DC!) m/e: 490 (MH*). 

Example 145 

25 

4-n[(5,6-Dihydro-5, 5-dimethyl>8-phenyl)-2-naphthalenyncart)onyl]aminol-2-hydroxybenzoic acid (l^j) 




Using the method for the preparation of the 8-phenyi derivatwe Ha. 193 mg (0.39 mmol) of compound Pj 
40 gave 135 mg (Y: 83%) of the title compound; iH-NMR (DlWSO-de): 6 11.33 (bs, 1H). 10.38 (s 1H) 7 83 (dd 
J=8.0. 1.7 Hz. 1H). 7.71 (d. J=8.7 Hz. 1H). 7.54 (d. J=8.0 Hz. 1H). 7.45-7.29 (m. 7H). 7.24 (dd! J=8!7. 1.8 Hz! 
1H). 6.06 (t. J=4.5 Hz, 1H), 2.35 (d, J=4.5 Hz. 2H) . 1.32 (s, 6H); MS (DCi) m/e: 400 (MH^; IR (KBr): 2960. 
1668,1600,1508. x / v / 

^ Anal, calcd. for C26H23N3O4 • 0.5 H2O: C. 73.92. H, 5.73; N. 3,32. Found: C, 73.91; H. 5.73; N. 2.99. 
Example 146 

2-Fluoro-4-nltrobenzolc add 




A solution of 2-fluoro-4-nitrotoluene (3.95 g, 25.5 mmol. Janssen) In water (200 mL) was treated portion- 
wise with potassium penmanganate (24.6 g. 0.15 mmol) at 80°C. After 2h the reaction mixture was filtered hot. 
acidified with 5N hydrochloric acid and extracted with ethyl acetate (2 x 100 mL). The extract was dried over 



78 



EP0 661 259 A1 



anhydrous sodium sulfate and concentrated in vacuo to give 1.15 g (Y: 24%) of the title compound; ^H-NMR 
(DMSO-de): 6 8^1 (d. J=10.5 Hz. 1H), 8.16-8.08 (m, 2H); MS (DCI) m/e: 186 (IVIH*). 

Example 147 

2-FluorD^nltroben2oic acid ethyl ester 



10 




To a solution of 2-fluoro-4-nitrobenzolc acid (1 .1 5 g, 6.22 mmol) In absolute ethyl alcohol (20 mL) was add- 
ed p-toluenesulfonic acid monohydrate (100 mg). After 16 h at reflux, the reaction mixture was concentrated 
in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate In hexane] to give 770 
mg (Y: 58%) of the tHIe product; ^H-NMR (CDaj: 8 8.16-8.00 (m. 3H). 4.45 (q. J=7.1 Hz. 2H). 1.43 (t. J«7.1 
Hz, 3H). MS (DCI) m/e: 214 (MH^. 

Example 148 

2-Fluoro-4-aminobenzoic acid ethyl ester 



30 




A solution of 2-fluoro-4-nitrobenzoic add ethyl ester (770 mg, 3.62 mmol) in methyl alcohol (15 mL) was 
treated with platinum (IV) oxide (75 mg) at 40 psi of Hj. After 0.5 h the reaction mixture was filtered through 
cellte and concentrated In vacuo to give 700 mg (Y: 99%) of the title product; 'H-NMR (CDCI3): 5 7.76 (t, J=8.3 
35 Hz. 1H), 6.42 (d. J=8.5 Hz, 1H). 6.35 (d. J=12.9 Hz. 1H), 4.33 (q. J=7.1 Hz, 2H), 4.20 (bs. 2H). 1.36 (t. J=7.1 
Hz, 3H); MS (DCI) m/e: 184 (MH^. 

Example 149 

^ ^•[I[(5.6-Dlhydro-5.5-dimethyl-8-phenyl)-2-naphthalenyllcarbonynamino)-2-fluorobenzolc acid ethyl ester 




Using the method given for the preparation of the 8-(2-fiuorophenyl) derivative l^g, 250 mg (0.90 mmol) 
55 of compound XVIIIa and 2-f luoro-4-aminobenzoic add ethyl ester (1 81 mg, 0.99 mmol) gave 240 mg (Y: 60%) 
of the title product; ^H-NMR (CDCfa): S 7.91 (t J=8.5 Hz. 1H). 7.72 (d. J=10.1 Hz. 1H). 7.66 (d. J=1.8 Hz. 1H). 
7.51-7.48(m, 1H), 7.44-7.35 (m, 6H), 7.20 (d, J=8.6 Hz. 1H). 6.08 (t, J=4.5 Hz, 1H). 4.37 (q, J=7.1 Hz, 2H) 
2.40 (d, JM.5 Hz. 2H), 1.38 (t. J=7.1 Hz. 3H), 1.37 (s. 6H); MS (DCI) m/e: 444 (MH^. 



79 



EP0 661 259 A1 

Example 150 

4-nf(5.6»Dlhydfo-5,SHjimethyl»e-phenyl)-2-naphthalenyOcaifaonyllaminol-2-fl^ acid (Kk) 



5 



10 




15 

Using the method given for the preparation of the 8-phenyl derivathre ha, 240 mg (0.54 mnwl) of compound 
1^ gave 175 mg (Y: 78%) of the title compound: ^H-NMR (DMSO-da): S 12.98 (bs. 1H). 10.58 (s. 1H), 7.89- 
7.77 (m. 2H). 7.73 (d. J=1.5 Hz, 1H). 7.54 (d. J=8.1 Hz, 1H). 7.44-7.30 (m. 7H), 6.06 (I. J=4.5 Hz. 1H), 2.34 (d, 
J=4.5 Hz. 2H). 1.31 (s, 6H). MS PCI) m/e: 416 (MH^; IR (KBr): 2960, 1692, 1596. 1526. 
20 Anal, caicd for C26H22N1O3F, • 0.25 H2O: C, 74.36; H. 5.40; N. 3.34. Found: C, 74.16; H, 5.74; N, 3.13. 

Example 151 

N-(4*Methyt-3-nltro-phenyt)acetamlde 

25 

H ^ 

A solution of 4-methyl-3-nItroanlline (3.60 g, 23.7 mmol) In acetic anhydride (28 mL) was allowed to stir 
at room temperature. After 16 h. the reaction mixture was concentrated in vacuo, diluted with ethyl acetate 
35 (25 mL), washed with saturated sodium bicarbonate (2 x 50 mL), dried over anhydrous sodium sulfate and con- 
centrated in vacuo to give 4.20 g (Y: 99%) of the title compound; ^H-NMR (CDCI3): 6 8.10 (d, J=1.7 Hz, 1H), 
7.75 (dd. J=8.5, 1.7 Hz, 1H), 7.38 (bs, 1H), 7.29 (d. J=8.5 Hz, 1H), 2.56 (s, 3H), 2.21 (s, 3H); MS (DCI) m/e: 
195 (MK*). 

40 Example 152 

4-Acetylamino-2-nitrobenzolc acid 



45 




Asolutlon of N-(4-methyi-3-nltro-phenyl)acetamide (4.20 g, 23.6 mnrK>I) In water (200 mL) was treated por- 
lionwise with potassium permanganate (22.77 g. 0.144 mmol) at 80^C. After 2 h the reaction mixture was fil- 
tered hot. acidified with 5N hydrochloric acid and extracted with ethyl acetate (2 x 100 mL). The extract was 
dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.80 g (Y: 34%) of the title compound; 
55 iH-NMR(CDCl3): 5 10.63 (s. 1H), 8.19 (d. J=1.7 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.78 (dd. J=8.5. 1.7 Hz, 1H), 
2.10 (s, 3H); MS (DCI) m/e: 225 (MH*). 



80 



EP0 661 259 A1 



Example 153 

4-Amino-2-nftrobenzoic acid ethyl ester 

6 



10 




A solutbn of 4-acetylamino-2-nitrobenzoic acid (1.80 g, fl.O mmol) in 12 N hydrochloric acid (14 mL) and 
absolute ethyl alcohol (10 mL) was heated to 90-100<'Cfor 5 h. Concentrated down in vacuo to remove ethyl 
alcohol only, adjusted pH to 4 with 1N sodium hydroxide and filtered off precipitate to give 140 mg (Y: 8%) of 
18 the title compound; ^H-NMR (CDaj: 6 7.81 (d, J=8.5 Hz, 1H). 6.82 (d. J=2.1 Hz. 1 H), 6.74 (dd. J=8.5, 2.1 Hz, 
1H). 6.52 (bs, 2H), 4.17 (q. J=7.1 Hz, 2H). 1.21 (t, J=7.1 Hz. 3H); MS (DCi) m/e: 211 (MH*). 

Example 154 

20 4-[n(5t6-D}hydro>5,5-dimethyl-8-phenyl)-2-naphthalenyl]carbonyf]amino]-2'n{trobenzoic acid, ethyl ester (W) 



25 



30 




Using the method given for the preparation of the 8-(2-fluorophenyl) derivative Pg, 199 mg (0.71 mmol) 
of compound XVllla and 140 mg (0.78 mmol) of 4-amino-2-nitrobenzoicacid ethyl ester gave 155 mg (Y:46%) 
35 of the title product; ^H-NMR (CDQa): 5 8.15 (s. 1H), 7.84 (s, 1H), 7.79 (s. 1H), 7.73 (dd, J=8.1, 1.9 Hz, 1H), 
7.52-7.49 (m. 2H), 7.41-7.26 (m. 5H), 6.09 (t, J=4.5 Hz. 1H). 4.36 (q, J=7.2 Hz, 2H), 2.40 (d, J=4.5 Hz, 2H), 
1.37 (s, 6H). 1.34 (I, J=7.2 Hz, 3H): MS (DCI) mfe: 471 (MH*). 

Example 155 

40 

4-[^(5.6-D^hydro-5,5-dimethyl-8-phenyl)-2-naphthaleny^carfaonyl]amino^2-nitrobenzoicacid (HI) 



45 



SO 




Using the method given for the preparation of the 8-phenyl derivative Ha. 155 mg (0.33 mmol) of compound 
55 |3| gave 105 mg (Y; 72%) of the title compound; ^H-NMR (DMSO-de): 6 13.65 (bs. 1H), 10.76 (s, 1H), 8.31 (d, 
J=1.7 Hz. 1H). 7.99 (dd, J=8.3, 1.7 Hz. 1H). 7.90-7.84 {nu 2H). 7.55 (d. J=a3 Hz, 1H), 7.47 (d. J=1.7 Hz, 1H). 
7.44-7.30 (m, 5H). 6.07 (t, J=4.5 Hz, 1H). 2.33 (d, J=4.5 Hz, 2H), 1.31 (s. 6H); MS (DCI) m/e: 443 (MH+); IR 
(KBr): 2960, 1702, 1542, 1518. 



81 



EP0 661 259 A1 



Anal, calcd. for C2BH22N2O5 • 0.5 H2O: C, 69.17, H. 5.14. N, 6.20. Found: C, 69.55. H. 4.93. N. 5.94. 
Example 156 

S 4-Q[(5,6'Dihydro>5,5-dimethyl-8-phenyl)-2-naphthalenyqcarbony1]aminch2-methoxyber^^ acid, methyl es- 
ter (Pm) 



10 



15 




Using the method for the preparation of the 8-(2-fluofophenyl) derivative t^g, 415 mg (1.49 mmol) of conv 
20 pound XVHIa and 297 mg (1 .64 mmol) of methyl 4-amlno-2-methoxybenzoate (Apin) gave 570 mg (Y: 90%) of 
the taie product; 'H-NMR(CDCl3): 6 7.82 (d. J=8.5 Hz, 1H). 7.77 (d. J=1.7 Hz, 1H).7.73 (s, 1H).7.70(d, J=1.9 
Hz. 1H). 7.51 (m, 1H), 7.48 (s, 1H).7.41-7.33 (m, 4H), 6.80 (dd, J=8.5, 1.9 Hz. 1H), 6.08 (t. J=4.5 Hz, 1H), 3.92 . 
(s. 3H). 3.87 (s. 3H). 2.39 (d, J=4.5 Hz, 2H). 1.38 (s, 6H); MS (DCI) m/e: 442 (MH^. 

25 Example 157 

4-[g(5.6*D[hydro-5.5-dlmethyl-8-phenyl)-2-naphthalenyncaffaonyl]aminol-2-methoxybenzolc add (Hm) 



30 



35 




40 Using the method given for the preparation of the a-phenyl derivative 1^, 135mg (0.31 mnK>l) of compound 

|3m gave 100 mg (Y: 77%) of the title compound: 'H-NIWR (DMSOnle): 5 12.32 (bs. 1H), 10.36 (s. 1H). 7.85 
(dd, J=8.1. 1.7 Hz, 1H). 7.79 (s, 1H). 7.64 (d. J=1.7 Hz, 1H). 7.53 (d, J=8.1 Hz. 1H), 7.44-7.30 (m. 7H). 6.06 
(t, J=4.5 Hz. 1H). 3.76 (s, 3H), 2.34 (d. J=4.5 Hz, 2H), 1.31 (s, 6H); MS (DCI) m/e: 428 (MH*); IR (KBr): 2960, 
1718. 1592. 1524. 

45 Anal, calcd for C27H25M,04 ■ 0.25 HjO: C, 75.07; H. 5.95; N, 3.24. Found: C, 75.04; H. 5.86; N. 3.04. 
Example 158 

4-|n(5.6-Pihydro-5.5-dimethyl-8-(2-naphthalene)l-2-naphtha}eny3carbonyl]amino3benzQic acid (hn) 



82 



EP0 661 259 A1 



5 



10 




Starting from compound XVIa the title compound was made from a method analogous to the preparation 
of the 8-(2-fluorophenyl) derivative l^g; ^H-NMR (DI^SO-d«): 5 12.69 (s. 1H), 10.41 (s, 1H). 7.95-7.88 (m, 5H), 
7.85 (d. J=8.7 Hz. 2H). 7.77 (d. J=8.7 H2.2H), 7.57-7.40 (m, 5H). 6.20 (t J=4.5 Hz. 1H), 2.40 (d. J=4.5 Hz. 2H). 
1.35 (s, 6H); MS (DCI) m/e: 448 (IWH*); IR (KBr): 2960, 1686. 1596. 1518. 

Anal, calod. for C30H2SO3N1 • 0.90 HjO: C, 77.70; H, 5.83; N, 3.02. Found: C, 78.10; H, 5.55; N, 3.13. 
Example 159 

4-[I(5.6-Dihydro-8-phenyl-2-naphthalenyl)carbonyl]amino]ben2oic acid (Ho) 



25 



30 




35 Starting from 6-methoxy tetraione the title compound was made from a method analogous to the prepa- 
ration of the 8-(2-fluorophenyl) derivative Kg; 'H-NMR (DMSO-de): 8 12.73 (s. 1H). 10.42 (s, 1H), 7.91-7.81 
(m, 5H). 7.55-7 J25 (m. 7 H), 6.18 (t, JM.5 Hz. 1H), 2.86 ft J=7.6 Hz. 2H). 2.41-2.34 (m, 2H); MS (DCI) m/e: 
370 (MH^; IR (KBr): 2950. 1680. 1648, 1518. 
Anal, calcd, for CaAHigNiOa : C. 78.03; H. 6.18; N. 3.79. 

40 Found: C, 77.61; H, 5.14; N. 3.81. 

Example 160 

Methyl 4-r[(5.6-dihydro-5,5-dimethyt-8-phenyl>2-naphthalenyl)carbonyi]amlno]-3-fluorobenzoate (1^) 



SO 



55 




Using the method given for the preparatton of the 8-(2-fluorophenyl) derivative l^g, compound XVIIIa (300 
mg) and methyl 3-fluoro-4-amInobenate (245 mg) gave 320 mg (69% yield) of the title compound as a glassy 

83 



EP0 661 259 A1 



mass; 1H-NMR (CDCI3) 6 1.38 (s. 6 H). 2.40 (d. J = 4.7 Hz. 2 H). 3.90 (s, 3 H), 6.08 (t. J = 4.7 Hz. 1 H). 7.32- 
7.42 (m. 5 H), 7.49 (d. J = 8 0 Hz. 1 H), 7.56 (d. J 0 1.9 Hz, 1 H). 7.73 (d. J = 1.9. 8.0 Hz, 1 H). 7.74 (d. J = 1.8. 
11.5 Hz, 1 H). 7.84 (dd, J = 1.8. 8.5 Hz. 1 H). 8.11 (bd, J 3.8 Hz, 1 H). 8.55 (t J = 8.5 Hz, 1 H). 

5 Example 161 

4-[I(5.6-Dihydro>5,5Hiimethyl-8-phenyl>2-naphthalenyl)carbonyf3amino}-3-fluofoben^^^ acid (Kp) 



10 



18 




20 Using the same method given for the preparation of the 8-phenyl derivative Ka. 310 mg of compound Pp 
gave 170 mg (54% yield) of the title compound; ^H-NMRtCDag) 6 1.23 (s. 6 H). 2.39 (d. J = 4.7 Hz, 2 H). 8.07 
(t, J = 4.7 Hz, 1 H). 7.30-7.42 (m, 5 H). 7.49 (d, J = 8.1 Hz. 1 H). 7.52 (d. J = 2.0 Hz , 1 H), 7.72 (d, J = 2.0, 8.1 
Hz. 1 H). 7.79 (d. J = 1.8. 11.4 Hz. 1 H), 7.90 (d. J = 8.5 Hz. 1 H), 8.06 (bd. J = 4.2 Hz. 1 H). 8.59 (t J = 8.6 
Hz, 1 H); MS m/e416(MH*). 

25 Anal. Calcd. for CaeH22FN03: C, 76.17; H, 5.34; N, 3.37. Found: C, 74.96; H. 5.53; N, 3.33. 

Example 162 

Methyl 4>ff(5,6-dihydro^5.5-dimethyl-8-phenyl-2^naphthalenyl)carfaonyl3amino^3-methylbenzoate(Pg) 



35 




Using the method given for the preparation of the B-(2-fluorophenyl) derivative l^g, compound XVIIIa (300 
mg) and methyl 3-methyl-4-aminobenate (319 mg) gave 305 mg (66 % yield) of the title compound as a glassy 
ntass; ^H-NMR (CDCy 6 1.39 (s. 6 H). 2.20 (s, 3 H). 2.41 (d, J = 4.7 Hz. 2 H), 3.89 (s, 3 H). 6.09 (t. J = 4.7 
45 Hz. 1 H). 7.30-7.45 (m. 5 H). 7.48 (d, J = 2.0 Hz. 1 H), 7.51 (d. J = 8.0 Hz. 1 H). 7.68 (s. 1 H). 7.79 (d. J = 2.0. 
8.0 Hz. 1 H). 7,85 (s. 1 H). 7.91 (dd. J = 2.0. 8.5 Hz. 1 H). 8.31 (d, J = 8.5 Hz. 1 H); MS m/e 426 (MH^. 
Anal. Calcd. for C28H27NOi0.125 HjO: C, 78.61; H, 6.42; N, 3.27. Found: C, 78.51; H. 6.46; N. 3.26. 

Example 163 

SO 

4'[r(5.6-Dihydro-5,5-dlmethyl>8"Phenyl»2-naphthalenyl)carbonyl3aminol-3-methylbenzofcac{d (Hg) 



84 



EP 0 661 259 A1 




10 



IS 



20 



25 



30 



3S 



40 



Using the same method gh/en for the preparation of the 8-phenyl derivative I4a, 280 mg of compound 1^ 
gave 223 mg (82 % yield) of the title compound; ^H-NMR (CDCIj) 5 1 .37 (s. 6 H), 2.20 (s. 3 H), 2.39 (d, J = 4.7 
Hz, 2 H), 6.07 (t, J = 4.7 Hz. 1 H), 7.30-7.42 (m. 5 H). 7.45 (d, J = 2.0 Hz, 1 H). 7.51 (d. J = 8.1 Hz, 1 H). 7.68 
(s. 1 H). 7.78 (d, J = 2.0, 8.1 Hz. 1 H), 7.80 (s. 1 H), 7.96 (dd, J = 1.9, 8.6 Hz. 1 H), 8.36 (d, J = 8.6 Hz. 1 H); 
MS m/e 412 (MH*). 

Anal. Calcd. for C27H25NO3: C, 78.81; H. 6.12; N. 3.40. 
Found: C. 78.68; H. 6.12; N. 3.40. 

This invention is further illustrated by the following biological tests, which are illustrative only. 

Rhino Mouse Study 

Representatives from compounds of formula I were tested for their effect on utriculi reduction on rhino 
mouse and directly compared to all-trans retinolc acid. 

Rhino mouse utriculi reduction assay 

Six to nine week old female hairless rhino mice {hf^fhr^) were produced in the Bristol-Myers Squibb col- 
ony. Test retinoids in ethanol vehicle (50ul) were applied to the dorsal area (approximately 1.5x3 cm^) of rhino 
mice once dally for 5 days (Monday to Friday). For various retinoids, a dose response was obtained with con- 
centrations ranging from 0.00033 mM to 16.5 mM. The animals were sacrificed on the following Monday by 
CO2 inhalation. A 7/8" full thickness punch was taken from the central dorsal area of each animal. The epi- 
dermis of the biopsy was removed from the dermis after incubation in 0.5% acetic acid overnight at 4**C. The 
separated epidermis was then f bced in formalin, dehydrated with ethanol. and cleared in xylene. To determine 
the utriculi diameter, each epidermis sheet was placed on a glass slide in xylene. For each specimen, the di- 
ameter of 40 utricules was measured with an image analysis system (IBM PC. Image Measure program and 
Olympus microscope with video camera). % Utriculi reduction was calculated as 



Since the maximum effect in this assay is approximately 60% utriculi reduction, the activity of various test 
compounds is reported as ED30 in Table 1, the concentration to reach 30% (half-maximum) utriculi reduction. 




Utriculi diameter in the test group \ 
utriculi diammeter m the ethanol control group] 




X 100% 



so 



ss 



85 



EP0 661 259 A1 

Table 1 



h 

Compound* 






1.25 


i«d 


0.931 


I*e 


0.123 


I«f 


0.C38 




2.35 


I"a 


0.86 


I*k 


3.12 



* The following compounds were not active in this 
Rhino mouse model: I'c, I"a, i"a, I"a, I'*e. 
I"a. I*p and rq 



The following bbiogical test indicates that the compounds of the instant invention possess cytotoxicity ac- 
tivity normally associated with retinoids. Thus in one aspect, the invention provides a method of treating various 
tumors. 

Cytotoxicity Result 

The cytotoxicity assay was set up similar to those run by the National Cancer Institute (D.A. Scudlero, et 
al, "Evaluation of a Soluble Tetrazolium/Formazan Assay for Ceil Growth and Drug Sensitivity In Culture Using 
Human and Other Tumor Cell Lines", Cancer Research, 48. 4827-4833, September 1 . 1 988; M. C. Alley, et al, 
"Feasibility of Drug Screening with Panels of Human Tunwr Cell Lines Using a Microculture Tetrazolium As- 
say", Cancer Research, 48, 589-601, February 1. 1988) with the exception that the new vital stain alamar- 
BLue™ was used to determine cellular viability. Briefly, the assayed mvoWed plating 1000 cells per well in a 
volume of 120 ^L In a 96 well flat-bottom dish (Corning) on day -1. Twenty-four hours later the appropriate 
dilution of a compound of formula I was added in a volume of 30 ^L complete medium (final volume 150 ^L). 
The plates were sealed with a plate sealer (Dynatech Labs) to prevent evaporation. On day 5 the mylar film 
was removed and 15 ^L of sterile alamarSlue was added to each well and the cells were incubated SV^C 5% 
CO2 for two hours. Using a Vmax plate reader the optical density for each well was determined having the 
OD670 subtracted from the ODgoo- The 100% signal was determined for cells grown in complete medium con- 
taining only 0.5% DMSO. All wells were set-up In triplicate and the mean values were plotted in Figures 1, 2 
and 3. The iCso values were determined for the second experiment and are listed in table 2. 



86 



EP0 661 259 A1 



TABLE 2 



IC50 values for L29a7 experiment 2 


Compound 


ICfiohiM) 


All trans retinoic acid 


68 


Ha 


51 


|ioa 


47 


Hfl 


38 


Hd 


28 


l»a 


60 


|2»a 


48 


l«a 


>100 


l^a 


28 



The compounds of formula I may be used topically or systemically, as anticancer agents and in the treat- 
ment, amelioration, or prevention of the skin disorders and rheumatic illnesses for which retinoic add and other 
retinoids are useful. In this regard, they may be used for therapy in animals, including humans, of promalignant 
epithelial cell lesions, as a prophylaxis against tumor pronation In epithelial cells and treatmentfor dermatoses 
2S such as Ichthyoses. follicular disorders, benign epithelial disorders, and other proliferative skin diseases (non- 
nmalignant conditions of the skin that are characterized by epidennal ceil proliferation or incomplete cell dif- 
ferentiation) such as acne, psoriasis, eczema, atopk: demiatitis, nonspecific dermatitis and the like. The conrv 
pounds of formula I may also be used In reversing and preventing the effects of Inradiation damage to skin. 
When used for the above treatments they will usually be formulated with a phanmaceutically acceptable liquW, 
semi-solid, or solid carrier. A pharmaceutlcally acceptable carrier is a material that Is nontoxic and generally 
Inert and does not affect the functionality of the active ingredients adversely. Such materials are well known 
and include those materials sometimes referred to as diluents or vehicles (excipients) in the pharmaceutical 
formulation art. The canrier may be organic or inorganic in nature. Examples of pharmaceutlcally acceptable 
earners that may be used to formulate a compound of formula I are water, gelatin, lactose, starch, mineral oil, 
cocoa butter, dextrose, sucrose, soitltoi. mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate. 
polyoxyethylene sorbttan monolaurate, and other commonly used pharmaceutical carriers. In addition to a com- 
pound of formula I and carrier, the formulatbn may contain minor amounts of addith/es such as flavoring 
agents, coloring agents, thickening or gelling agents, emulsif lers, wetting agents, buffers, stabilizers, and 
preservatives such as antioxidants. 

The dosages and dosage regimen in which the compounds of formula I are administered will vary according 
to the dosage forni, mode of administratton, the condltton being treated and partk:ulars of the patient being 
treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through 
routine experimentation. 

In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in 
certain cases such as treatment of severe cystic acne, oral administration may also be used. If the compounds 
according to the invention are used topically, it will be found that they exhibit a good activity over a very broad 
range of dilution; in particular, concentrations of the active compound or compounds ranging from 0.0005% 
to 2% by weight can generally be used. It is of course possible to use higher concentrations if this should be- 
come necessary for a particular application; however, the preferred concentration of active principle are from 
0.002% lo1% by weight 

For topical administratton the compounds of fonmula I are conveniently provided in the fonm of unguents, 
gels, creams, ointments, powders, dyeing compositions, solutions, suspensions, emulsions, lotions, sprays, 
adhesive plasters and impregnated pads. The compounds according to the invention can be mixed with inert 
nontoxic, generally liquid or pasty, bases suitable for topical treatment Preparation of such topical fonmulatfons 
are well described in the art of pharnrtaceutical formulations as exemplified, for example. Remington's Phar- 
maceutical Science. Editton 17, Mack Publishing Company, Easton, Pa. Other medfcaments can be added to 
such topical formulation for such secondary purposes as treating skin dryness, providing protection against 
light; other medications for treating dermatoses, preventing infection, reducing initation, inflammation and the 



87 



EP 0 661 259 A1 

like. 



20 



25 



30 



35 



40 



4$ 



s£~?rr=^~-.==Kss;ra;- 



50 



Claims 

1- Acompound of formula I 



55 



88 



EP0 661 259 A1 




R"* and 
n 



R« and R» 



Z 

R^ R« and Ry 



-CR5=CRe.; ''"^"^•^'*^'-CHiS-.-CH20...0CHr,-NHCHror 

•(CHJrY. Ci^lkyl. or Cj^cycloalkyl; 

and R3 "CONHRy. or CHO; 

afB independently hydrogen or C,^ky|- 

c ■ 

Is hydrogen or Ci_ealkyl; 
are Independently hydrogen or C^^alkyl; and 
is zero to six. 

4-I[(5.6.dfhyd,o-5 S-dimeZ B TTl ''^^^.^"^'^''^^'^ ^c^d; 
4-I[(5.6-dihydro-5.5.6-.r.n,eCC.^Sn?^^^^^^ 

4-[r(5,6-dihydro-5.5,7-trimethvl-B.nhpn!^ o "^P^"^^'*"y')«*«'"yllamino]bBn2oic acid; 

4-nr(5.e.-diM«.-5.5-dimethy)-i^5henySLhS^^^^ 
4-ffl(5,6-dihydro-5.5-dimethl8-nE 2 „?nSL f 



89 



EP0 661 259 A1 



4-ni{5.6^ihydro-5.5-diinethyl-8-Dhenv^» 3 T^,'^ "^'^""^^^-nitrobenzoic acid; 

4-ni(5.6Klihyd«^S.5.dime hS-ShS^^^ 

^'r<^-«-''M-5.5^.methy,.8-pheny,-2-„aph.ha,en^^^ . 
4-ff(5.6.,,hydro-5.5^,.ethy.8-pHen,.^„apH,ha,eny,^^^^ ' 
form a radical of the formula - * » -conh-. R2 and R» are methyl; and R« and Rt» together 




A compound of daim 1 in which Rt Is -CO.H; n is zero; and Ra and R3 are .ethy, 
2.compou„d,of.a,mewhichare4-a(1.1.ime.^^^^^^^^ 

l£ 1 T^^'^''''^"y^^"-''«*«"-5-yOvinylIben2Bic acid- and 
4-[(1.1-dlmethy,.3-phe„y,.,H-inden^5.cart,oi!,amln<;bjS;J?cld. 
A Pharmaceutical compositton comprfei„g a compound as claimed in daim 1. 

The^ u.e of a compound as claimed l„ daim 1 for prepanng a pharmaceu.^ opposition for treating a 



90 



EP0 661 259 A1 




91 



EP 0 661 259 A1 




EP0 661 259 A1 




EP 0 661 259 A1 



Europeu Patnt 
Office 



EUROPEAN SEARCH REPORT 



DOCUMENTS CONSIDERED TO Iti^^T^^ 



A,0 



US-A-3 973 030 (ROBERT MATHEWS BOWMAN ET 

* abstract * 

m^mdV^) f-ieANo'pWEUTICALS 

• claims 1-5 » 

•"abstract^" (SRI INTERNATIONAL) 

JOURNAL OF MEDICINAL CHDIISTRY. 
vol.31, 1988, WASHINGTON US 
pages 2182 - 2192 

HIROYUKI KAGECHIKA ET AL. 'Retinobenzoic 
• the whole document * 

EURDPEWJ JOURNAL OF MEDICINAL 
CHEMISTRY.CHIMICA THeSJeJuEa, 
vol.15 no.l. 1980. PARIS FR 
pages 9-15 

PETER LOELIGER ET AL. 'Arotinolds. a new 
class of highly active retinoid" 
the vrhole document * 



I report kif hetm Amn 19 fer ig| MmSm„ 



1.8 

1.8.9 

1.8.9 
1.8,9 



1.8,9 



BERLIN 



CATECOKV OF OTED OOCUMENIS 

Pi 



19 April 1995 



EP 95 10 0033 



C07C233/81 

C07C235/84 

C07C69/76 

C07C63/66 

C07C327/32 

C07C327/26 

C07C323/22 

C07C327/48 

C07C229/60 

C07C229/38 

C07C65/38 

C07C69/92 

C07C59/72 

A61K31/165 

A61K31/19 

A61K31/235 

A61K3 1/265 



TECHNICAL FQUIS 



C07C 
A61K 



Rufet, J 



D: 



dMIalfcta . 



94